Compositions containing non-polar compounds

ABSTRACT

Provided herein are compositions and methods for preparing foods and beverages that contain additives, such as nutraceuticals, pharmaceuticals, and supplements, such as essential fatty acids, including omega-3 fatty acids, omega-6 fatty acids, conjugated fatty acids, and other fatty acids; phytochemicals, including phytosterols; other oils; and coenzymes, including Coenzyme Q10, and other oil-based additives.

RELATED APPLICATIONS

Benefit of priority is claimed under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 61/070,392, filed Mar. 20, 2008,entitled “COMPOSITIONS CONTAINING NON-POLAR COMPOUNDS,” and U.S.Provisional Application Ser. No. 61/132,409, filed Jun. 16, 2008,entitled “COMPOSITIONS CONTAINING NON-POLAR COMPOUNDS,” each to PhilipBromley.

This application is related to International Application No.PCT/US09/001,774, filed Mar. 20, 2009, entitled “COMPOSITIONS CONTAININGNON-POLAR COMPOUNDS,” which also claims priority to U.S. ProvisionalApplication Ser. Nos. 61/070,392 and 61/132,409. This application alsois related to U.S. patent application Ser. No. 12/373,244, filed Mar.20, 2009, entitled “COMPOSITIONS CONTAINING NON-POLAR COMPOUNDS” andInternational Application No. PCT/US09/001,775, filed Mar. 20, 2009,entitled “COMPOSITIONS CONTAINING NON-POLAR COMPOUNDS,” which claimpriority to U.S. Provisional Application Ser. No. 61/070,381, filed Mar.20, 2008, entitled “COMPOSITIONS CONTAINING NON-POLAR COMPOUNDS,” andU.S. Provisional Application Ser. No. 61/132,424, filed Jun. 16, 2008,entitled “COMPOSITIONS CONTAINING NON-POLAR COMPOUNDS,” each to PhilipBromley.

The subject matter of each of the above-referenced applications isincorporated by reference in its entirety.

FIELD OF THE INVENTION

Provided are compositions and methods for preparing foods and beveragesthat contain additives, such as nutraceuticals, pharmaceuticals, andsupplements, such as essential fatty acids, including omega-3 fattyacids, omega-6 fatty acids, conjugated fatty acids, and other fattyacids; phytochemicals, including phytosterols; other oils; andcoenzymes, including Coenzyme Q10, and other oil-based additives.

BACKGROUND

Non-polar compounds are not easily dissolved in aqueous solutions, suchas water. A number of non-polar compounds are used in compositions forhuman ingestion, for example, pharmaceuticals, nutraceuticals and/ordietary supplements. Exemplary of non-polar compounds used in suchcompositions are vitamins and minerals, fatty acids, and other non-polarcompounds, non-polar active agents and non-polar active ingredients.

Because of poor water solubility, use of non-polar compounds in productsfor human consumption, for example, supplements, foods and beverages,often is challenging. Available compositions containing non-polarcompounds, particularly aqueous compositions containing non-polarcompounds, and methods for formulating such compositions, are limited.For example, methods and compositions for providing non-polar compoundsin aqueous solutions, for example, in emulsions, are limited.

Thus, there remains a need to develop alternate compositions containingnon-polar compounds and methods for making the compositions.Accordingly, it is among the objects herein to provide compositions,including solid and semi-solid compositions and aqueous compositions,containing non-polar compounds (e.g. non-polar active ingredients), andmethods for making the compositions.

SUMMARY

Provided are first compositions (pre-emulsion compositions) that containnon-polar compounds. Typically, the first compositions are non-aqueouspre-emulsion compositions. Also provided are methods that use such firstcompositions to prepare other compositions, such as beverages and otheraqueous liquids, into which the first compositions are diluted. Alsoprovided are liquid dilution compositions containing the beverage orother aqueous liquid and the diluted pre-emulsion composition. Thepre-emulsion compositions can be used to prepare dispersions, such asbeverages, containing effective amounts of additives, such as non-polarcompounds. The dispersions (e.g. liquid dilution compositions) can beused to provide an effective amount of the non-polar compounds,including non-polar active ingredients, such as nutraceuticals,pharmaceuticals, and supplements, such as essential fatty acids,including polyunsaturated fatty acids, such as omega-3 fatty acids,omega-6 fatty acids, conjugated fatty acids, and other fatty acids;phytochemicals, including phytosterols; other oils; and coenzymes,including Coenzyme Q10; and other oil-based additives. The amounts inthe resulting diluted compositions are effective to supplement the diet.The compositions provided herein are and/or can be used to producestable dispersions, without phase separation and other changes, such asparticle formation, crystal formation and/or ringing.

The pre-emulsion compositions, for example, the non-aqueous pre-emulsioncompositions, contain one or more surfactants (typically a surfactantthat is a polyethylene glycol (PEG)-derivative of Vitamin E) and anon-polar compound (typically a non-polar active ingredient) other thanthe surfactant. In one example, where the pre-emulsion composition is anon-aqueous pre-emulsion composition, not more than 5% or about 5%, ornot more than 1% or about 1%, by weight, of the composition, containshydrophilic ingredient(s). Typically, the non-aqueous pre-emulsioncomposition has a waxy consistency.

In one embodiment, the amount of non-polar active ingredient is between5% or about 5% and 35% or about 35%, for example, at or about 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34 or 35%, by weight, of thepre-emulsion composition and the amount of the surfactant is between 65%or about 65% and 95% or about 95%, for example, at or about 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94 or 95%, by weight, of thepre-emulsion composition.

In one example, the amount of surfactant is between 69% or about 69% and90% or about 90%, by weight, of the composition, for example, between69% or about 69% and 80% or about 80%, by weight, or between 79% orabout 79% and 90% or about 90%, by weight, of the composition, or 69.5%or about 69.5%, 79.5% or about 79.5%, or 89.5% or about 89.5%, byweight, of the composition.

In another example, the amount of the non-polar active ingredient isbetween 10% or about 10% and 30% or about 30%, between 20% or about 20%and 30% or about 30% or between 10% or about 10% and 20% or about 20%,by weight, of the composition, for example, at or about 10%, 20%, or30%, by weight, of the composition.

In one example of this embodiment of the provided pre-emulsioncompositions, where the amount of the surfactant is between 69% or about69% and 80% or about 80%, by weight, of the composition, the non-polaractive ingredient is between 20% or about 20% and 30% or about 30%, byweight, of the composition. In one embodiment, where the amount of thesurfactant is between 79% or about 79% and 90% or about 90%, by weight,of the composition, the amount of the non-polar active ingredient isbetween 10% or about 10% and 20% or about 20%, by weight, of thecomposition.

In one example, the amount of surfactant is 69.5% or about 69.5%, byweight, of the composition and the amount of non-polar active ingredientis 30% or about 30%, by weight, of the composition; or the amount ofsurfactant is 79.5% or about 79.5%, by weight, of the composition andthe amount of non-polar active ingredient is 20% or about 20%, byweight, of the composition; or the amount of surfactant is 89.5% orabout 89.5%, by weight, of the composition and the amount of non-polaractive ingredient is 10% or about 10%, by weight, of the composition.

In another embodiment of the provided pre-emulsion compositions, thefurther contains at least one additional non-polar active ingredient. Inone example of this embodiment, the combined weight of the non-polaractive ingredient and the at least one additional active ingredient isless than 30% or about 30%, or less than 50% or about 50%, of the weightof the non-aqueous pre-emulsion composition.

In another embodiment, the provided pre-emulsion composition contains anon-polar active ingredient at an amount between 5% or about 5% and 15%or about 15%, by weight, of the pre-emulsion composition, and asurfactant at an amount of between 40% or about 40% and 60% or about60%, by weight, of the pre-emulsion composition. In one aspect of thisembodiment, the non-polar active ingredient contains a phytosterol. Inone example of this embodiment, the amount of the surfactant is between49% or about 49% and 55% or about 55%, by weight, of the pre-emulsioncomposition. In one example of this embodiment, the pre-emulsioncomposition further contains one or more solvent one or more additionalnon-polar active ingredients, or a combination thereof. Exemplary of theone or more solvents, one or more additional non-polar activeingredients, and/or combinations thereof are compounds selected fromamong any one or more of Vitamin E oil, flaxseed oil, CLA and saffloweroil.

In one embodiment, the provided pre-emulsion composition consistsessentially of the non-polar active ingredient and the surfactant. Inother embodiments, the pre-emulsion composition consists essentially ofthe non-polar active ingredient, the surfactant and a preservative. Inanother embodiment, the pre-emulsion composition consists essentially ofthe non-polar active ingredient, the surfactant, a preservative, and asolvent.

Typically, the surfactant(s) in the provided pre-emulsion compositionshas an HLB value of between 14 or about 14 and 20 or about 20, forexample, at or about 14, 15, 16, 17, 18, 19 or 20, typically between 16or about 16 and 18 or about 18. Exemplary surfactants include, but arenot limited to, Vitamin E-derived surfactants, such as tocopherol and/ortocotrienol-derived surfactants, in which the Vitamin E moietyrepresents the hydrophobic region of the surfactant, and is attached,via a linker, to another moiety, such as a polyethylene glycol (PEG)moiety. Exemplary of the Vitamin-E derived surfactants that can be usedin the pre-emulsion compositions include, but are not limited to,tocopherol derived surfactants, including polyalkylene glycolderivatives of tocopherol, typically polyethylene glycol (PEG)derivatives of tocopherol, such as tocopherol polyethylene glycolsuccinate (TPGS), TPGS analogs, TPGS homologs and TPGS derivatives.Alternatively, the surfactants can be other PEG derivatives havingsimilar properties, for example, PEG derivatives of sterols, e.g. acholesterol or a sitosterol (including, for example, any of the PEGderivatives disclosed in U.S. Pat. No. 6,632,443) or PEG-derivatives ofother fat-soluble vitamins, for example, some forms of Vitamin A (e.g.Retinol) or Vitamin D (e.g. Vitamin D1-D5).

An exemplary surfactant that can be used in any of the providedpre-emulsion compositions is a polyethylene glycol (PEG)-derivative ofVitamin E, for example, a tocopherol polyethylene glycol diester (TPGD).In one embodiment, the TPGD is selected from among tocopherol sebacatepolyethylene glycol, tocopherol dodecanodioate polyethylene glycol,tocopherol suberate polyethylene glycol, tocopherol azelaatepolyethylene glycol, tocopherol citraconate polyethylene glycol,tocopherol methylcitraconate polyethylene glycol, tocopherol itaconatepolyethylene glycol, tocopherol maleate polyethylene glycol, tocopherolglutarate polyethylene glycol, tocopherol glutaconate polyethyleneglycol and tocopherol phthalate polyethylene glycol. In one embodiment,the surfactant is a tocopherol polyethylene glycol succinate (TPGS),such as a TPGS-1000 and/or a d-α TPGS. In another embodiment, thesurfactant is a TPGS analog. In one aspect, the surfactant is a TPGShomolog, such as, for example, a TPGS homolog that differs from a TPGSparent compound by the addition or removal of one or more methyleneunit(s), e.g., —(CH₂)_(n)—.

In some embodiments of the provided pre-emulsion compositions, the PEGmoiety in the PEG-derivative of Vitamin E surfactant is selected fromamong any one or more of methylated PEG (m-PEG), PEG-OH, PEG-NHS,PEG-aldehyde, PEG-SH, PEG-NH₂, PEG-CO₂H, methylated PEGS and branchedPEGs. In some embodiments, the PEG moiety in the surfactant has amolecular weight of between 200 or about 200 to 20,000 or about 20,000Da, between 200 or about 200 and 6000 or about 6000 Da, between 600 orabout 600 Da and 6000 or about 6000 Da, between 200 or about 200 Da and2000 or about 2000 Da, between 600 or about 600 Da and 1500 or about1500 Da, or between 600 or about 600 and 1000 or about 1000 Da.

Exemplary of non-polar compounds that can be included in any of theprovided pre-emulsion compositions are non-polar active ingredients.Exemplary non-polar active ingredients include, but are not limited toomega-3 fatty acids, omega-6 fatty acids, conjugated fatty acids,Coenzyme Q10 (e.g. ubidecarenone), phytosterols and saw palmettoextracts, such as, for example, fish oil, algae oil, flaxseed oil, GLA(e.g. borage oil) and CLA.

Also exemplary of the non-polar active ingredients include, but are notlimited to, compounds containing any fat-soluble nutraceutical orpharmaceutical and/or oil, such as, for example, drugs, hormones,vitamins, nutrients, including any and other lipophilic compoundscontaining essential fatty acids, for example, polyunsaturated fattyacids (PUFAs), including, for example, omega-3 fatty acids, for example,natural and synthetic omega-3 fatty acids, for example, compoundscontaining omega-3 polyunsaturated long-chain fatty acids, includingEicosapentaenoic acid (EPA) (20:5{acute over (ω)}3); Docosahexaenoicacid (DHA) (22:6{acute over (ω)}3); Eicosatetraenoic acid (24:4{acuteover (ω)}3); Docosapentaenoic acid (DPA, Clupanodonic acid) (22:5{acuteover (ω)}3); 16:3{acute over (ω)}3; 24:5{acute over (ω)}3 and/or nisinicacid (24:6{acute over (ω)}3), for example, fish oil, algae oil, krilloil, canola oil, flaxseed oil, soybean oil and walnut oil; compoundscontaining short-chain omega-3 fatty acids, for example, Alpha-Linolenicacid (α-Linolenic acid; ALA) (18:3{acute over (ω)}3) (e.g. flaxseed oil)and Stearidonic acid (18:4{acute over (ω)}3), esters of an omega-3 fattyacid and glycerol, for example, monoglycerides, diglycerides andtriglycerides, esters of omega-3 fatty acid and a primary alcohol, forexample, fatty acid methyl esters and fatty acid esters, precursors ofomega-3 fatty acid oils, for example, EPA precursor, DHA precursor,derivatives such as polyglycolized derivatives or polyoxyethylenederivatives, oils containing the omega-3 fatty acids, for example, fishoil (marine oil), for example, highly purified fish oil concentrates,perilla oil, krill oil, and algae oil, for example, microalgae oil;compounds containing omega 6 fatty acids, for example, compoundscontaining Linoleic acid (18:2{acute over (ω)}6) (a short-chain fattyacid); Gamma-linolenic acid (GLA) (18:3{acute over (ω)}6); Dihomo gammalinolenic acid (DGLA) (20:3{acute over (ω)}6); Eicosadienoic:acid(20:2{acute over (ω)}6); Arachidonic acid (AA) (20:4{acute over (ω)}6);Docosadienoic acid (22:2{acute over (ω)}6); Adrenic acid (22:4{acuteover (ω)}6); and/or Docosapentaenoic acid (22:5{acute over (ω)}6), forexample, borage oil, corn oil, cottonseed oil, grapeseed oil, peanutoil, primrose oil, for example, evening primrose Oenothera biennis) oil,blackcurrant seed oil, hemp seed oil, spurulina extract, safflower oil,sesame oil and soybean oil;

compounds containing other fatty acids, for example, triglycerides,including medium chain triglycerides, polar lipids, for example, etherlipids, phosphoric acid, choline, fatty acids, glycerol, glycolipids,triglycerides, and phospholipids (e.g., phosphatidylcholine (lecithin),phosphatidylethanolamine, and phosphatidylinositol); saw palmettoextract; and ethyl linoleate; and herb oils, for example, garlic oilsand scordinin; short-chain saturated fatty acids (4:0-10:0), Lauric acid(12:0), Myristic:acid (14:0), Pentadecanoic acid (15:0), Palmitic acid(16:0), Palmitoleic acid (16:1 ω7), Heptadecanoic acid (17:0), Stearicacid (18:0), Oleic acid (18:1 ω9), Arachidic:acid (20:0);

compounds containing micronutrients, for example, vitamins, minerals,co-factors, for example, coenzymes, such as coenzyme Q, e.g. CoenzymeQ10 (CoQ10, also called ubiquinone, e.g. ubidecarenone or a reduced formof CoQ10, e.g. ubiquinol), tumeric extract (cucuminoids), saw palmettolipid extract (saw palmetto oil), echinacea extract, hawthorne berryextract, ginseng extract, lipoic acid (thiotic acid), acsorbylpalmitate, kava extract, St. John's Wort (hypericum, Klamath weed, goatweed), extract of quercitin, dihydroepiandrosterone, indol-3-carbinol;

compounds containing carotenoids, including hydrocarbons and oxygenated,alcoholic derivatives of hydrocarbons, for example, beta carotene, mixedcarotenoids complex, leutein, lycopene, Zeaxanthin, Cryptoxanthin, forexample, beta-crytoxanthin, astaxanthin, bixin, canthaxanthin,capsanthin, capsorubin, apo-carotenal, beta-12′-apo-carotenal,“Carotene” (mixture of alpha and beta-carotene), gamma carotene,ciolerythrin, esters of hydroxyl- or carboxyl-containing membersthereof;

compounds containing fat-soluble vitamins, for example, Vitamins A, D, Eand K, and corresponding provitamins and vitamin derivatives such asesters with an action resembling that of vitamin A, D, E or K forexample; retinol (vitamin A) and pharmaceutically acceptable derivativesthereof, for example, palmitate ester of retinol and other esters ofretinol, and calciferol (vitamin D) and its pharmaceutically acceptablederivatives thereof and precursors of vitamin D, d-alpha tocopherol(vitamin E) and derivatives thereof, including pharmaceuticalderivatives thereof, for example, Tocotrienols, d-alpha tocopherolacetate and other esters of d-alpha tocopherol, and ascorbyl palmitate,a fat-soluble version of vitamin C;

compounds containing phytochemicals, including phytoestrogens, forexample, genistein and daidzein, for example, isoflavones, for example,soy isoflavones, flavonoids, phytoalexins, for example, Resveratrol(3,5,4′-trihydroxystilbene), red clover extract, and phytosterols;

compounds containing lipid-soluble drugs, including natural andsynthetic forms of immunosuppressive drugs, such as Cyclosporin,protease inhibitors such as Ritonavir, macrolide antibiotics and oilsoluble anesthetics such as Propofol, natural and synthetic forms ofsteroidal hormones, for example, estrogens, estradiols, progesterone,testosterone, cortisone, phytoestrogens, dehydroepinadrosterone (DHEA),growth hormones and other hormones;

compounds containing oil-soluble acids and alcohols, for example,tartaric acid, lactylic acid butylated hydroxyanisole, butylatedhydroxytoluene, lignin, sterols, polyphenolic compounds, oryzanol,cholesterol, phytosterols, flavonoids, such as quercetin and reservatol,diallyl disulfides and the like.

In some embodiments, the non-polar active ingredient includes one ormore of polyunsaturated fatty acids, such as compounds including any oneor more of omega-3 fatty acids, including Docosahexaenoic acid (DHA),eicosapentaenoic acid (EPA) and alpha-linolenic acid (ALA) (for example,fish oils, krill oils, algae oils and/or flaxseed oils); omega-6 fattyacids, such as gamma-linolenic acid (GLA) (e.g. borage oils); conjugatedfatty acids (e.g. conjugated linolenic acid (CLA)); and saw palmettoextracts. In other embodiments, the non-polar active ingredients includecompounds containing coenzymes, typically coenzyme Q, for example,Coenzyme Q10, e.g. ubidecarenone, and/or compounds containingphytosterols.

In any of the provided pre-emulsion compositions, the non-polar activeingredient contains EPA, DHA or a combination thereof. In one aspect,the non-polar active ingredient contains DHA, at an amount between 20%or about 20% and 90% or about 90% or between 25% or about 25% and 85% orabout 85%; or between 35% or about 35% and 70% or about 70%, or between25% or about 25% and 40% or about 40%, by weight, of the non-polaractive ingredient. In another aspect, the non-polar active ingredientcontains EPA, at an amount between 5% or about 5% and 15% or about 15%,between 5% or about 5% and 13% or about 13%, or between 5% or about 5%and 10% or about 10% by weight, of the non-polar active ingredient. Inone aspect, the amount of EPA is not more than 10% or about 10%, or notmore than 13% or about 13%, by weight, of the non-polar activeingredient. In exemplary embodiments, the non-polar active ingredient isa fish oil or an algae oil.

In one embodiment, the non-polar active ingredient contains ALA, at anamount of at least 50% or about 50%, by weight, of the non-polar activeingredient, such as between 50% or about 50% and 80% or about 80%, orbetween 65% or about 65% and 75% or about 75%, by weight, of thenon-polar active ingredient. Exemplary of such an embodiment is apre-emulsion composition containing a flaxseed oil.

In another embodiment, the non-polar active ingredient contains GLA atan amount of at least 22% or about 22%, by weight, of the non-polaractive ingredient, for example, in a borage oil.

In some embodiments, the pre-emulsion compositions contain more than onenon-polar active ingredient, for example, two or more non-polar activeingredients where the total amount of non-polar active ingredient isbetween at or about 5% and 35% of the weight of the pre-emulsioncomposition, or between at or about 5% and 15% of the pre-emulsioncomposition, for example, where the combined weight of the non-polaractive ingredient and additional non-polar active ingredient(s) is lessthan at or about 35%, 30%, or 15%, by weight, of the pre-emulsioncomposition.

The provided pre-emulsion compositions further can contain one or moreadditional ingredients. In one embodiment, the compositions furthercomprise one or more preservative, in an amount sufficient to preservethe composition. Exemplary of the preservatives are naturalpreservatives, such as benzyl alcohol and preservatives containingbenzyl alcohol. In one embodiment, the amount of preservative is between0.1% or about 0.1% and 1% or about 1%, by weight, of the pre-emulsioncomposition, for example, at or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9 or 1%, by weight of the composition. In one example, the amountof benzyl alcohol is between 0.1% or about 0.1% and 1% or about 1%, byweight, of the pre-emulsion composition, for example, at or about 0.1,0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1%, by weight of thepre-emulsion composition.

In another embodiment, the one or more additional ingredients includes asolvent that dissolves the non-polar active ingredient and differstherefrom. In one example, the amount of solvent is sufficient todissolve the non-polar active ingredient. Exemplary of the solvents areoils. The solvent(s) can include any oil suitable for dissolving thenon-polar ingredient. Exemplary of the solvents are Vitamin E oil,flaxseed oil, sunflower oil, any vegetable oil or other oil. In oneembodiment, the amount of solvent in the concentrate is between 1% orabout 1% and 6% or about 6%, for example, at or about 1, 2, 3, 4, 5, or6%, by weight, of the composition.

In another embodiment, the one or more additional ingredients includesone or more emulsion stabilizers. Typically, the emulsion stabilizer isincluded in the composition at an amount sufficient to stabilize thecomposition. Exemplary of an emulsion stabilizer is a compositioncontaining a blend of gums, such as the Saladizer® brand emulsionstabilizer. In one embodiment, the emulsion stabilizer contains one ormore of guar gum, xanthan gum and sodium alginate. In one example, theemulsion stabilizer contains guar gum, xanthan gum and sodium alginate.

In another embodiment, the one or more additional ingredients includeone or more co-surfactants. In one example, the co-surfactant isincluded in the pre-emulsion composition in an amount sufficient tostabilize the composition. In one aspect, the co-surfactant is aphospholipid, such as, but not limited to, a phosphatidylcholine. In oneexample, the amount of the co-surfactant, e.g. the phospholipid, isbetween 0.1% or about 0.1% and 1% or about 1%, by weight, of theconcentrate.

In another embodiment, the one or more additional ingredients includesone or more flavors. In one example, the flavor is included in thecomposition at an amount sufficient to enhance the taste of thecomposition, the smell of the composition, or a combination thereof.Exemplary flavors include, but are not limited to, lemon oil,D-limonene, or a combination thereof, or any other known flavors, suchas flavors described herein.

Also exemplary of the additional ingredients that can be included in theprovided compositions are one or more pH adjusters. Typically, the pHadjuster contains an acid or a base at an amount sufficient to affectthe pH of the compositions. Exemplary of the pH adjusters are citricacid and phosphoric acid.

In some embodiments, the pre-emulsion composition is formulated based onthe properties of dilution compositions that can be generated bydiluting the pre-emulsion composition in an aqueous liquid. Typically,the pre-emulsion composition is formed so that it can be diluted inaqueous medium to produce a liquid dilution composition having one, morethan one, all, or any combination of, of the following properties:

In one embodiment, the pre-emulsion composition is formulated such that:dilution of at least 0.5 g or about 0.5 g, at least 1 g or about 1 g, atleast 2 g or about 2 g, at least 5 g or about 5 g, or at least 10 g orabout 10 g of the pre-emulsion composition into at or about 8 fluidounces (0.236588 liters) of an aqueous medium; or dilution of thepre-emulsion composition in an aqueous medium, at a dilution of not morethan 1:10 or about 1:10, not more than 1:25 or about 1:25, not more than1:50 or about 1:50, not more than 1:100 or about 1:100, not more than1:250 or about 1:250 or not more than 1:500, yields a liquid dilutioncomposition having a particle size of less than 500 or less than about500, less than 300 or less than about 300 or less than 200 nm or lessthan about 200 nm, on the average or at the most.

In one embodiment, the liquid dilution composition that is formed bydilution of the pre-emulsion composition into aqueous medium has aparticle size of less than 500 or less than about 500, less than 300 orless than about 300 or less than 200 nm or less than about 200 nm, onthe average or at the most, and contains at least 25 mg or about 25 mg,at least 35 mg or about 35 mg, at least 50 mg or about 50 mg or at least100 mg or about 100 mg, at least 250 mg or about 250 mg, or at least 500mg or about 500 mg of the non-polar active ingredient per 8 fluid ouncesof the liquid dilution composition.

In some aspects of these embodiments, the resulting liquid dilutioncomposition that is formed by diluting the pre-emulsion composition hasa particle size of less than 100 nm or about 100 nm, less than 50 nm orabout 50 nm, less than 25 nm or about 25 nm, less than 15 nm or about 15nm or less than 10 nm or about 10 nm, on average or at the most.

In another embodiment, the pre-emulsion composition is formulated suchthat dilution of at least 0.5 g or about 0.5 g, at least 1 g or about 1g, at least 2 g or about 2 g, at least 5 g or about 5 g, or at least 10g or about 10 g of the pre-emulsion composition into 8 or about 8 fluidounces of an aqueous medium; or dilution of the concentrate in anaqueous medium, at a dilution not more than 1:10 or about 1:10, not morethan 1:25 or about 1:25, not more than 1:50 or about 1:50, not more than1:100 or about 1:100, not more than 1:250 or about 1:250 or not morethan 1:500, yields a liquid dilution composition having a NephelometricTurbidity Units (NTU) value of less than 500 or about 500, less than 300or about 300, or less than 200 or about 200. In one aspect, the NTUvalue of the resulting dilution composition is less than 100 or about100, less than 50 or about 50, less than 30 or about 30, less than 25 orabout 25, or less than 10 or about 10.

In another embodiment, the liquid dilution composition formed bydilution of the pre-emulsion composition into aqueous medium has an NTUvalue of less than 500 or about 500, less than 300 or about 300, or lessthan 200 or about 200 and contains at least 25 mg or about 25 mg, atleast 35 mg or about 35 mg, at least 50 mg or about 50 mg, at least 100mg or about 100 mg, at least 250 mg or about 250 mg, or at least 500 mgor about 500 mg of the non-polar active ingredient per 8 fluid ounces ofthe liquid dilution composition.

In some aspects of these embodiments, the NTU value is less than 100 orabout 100, less than 50 or about 50, less than 30 or about 30, less than25 or about 25, or less than 10 or about 10.

In another embodiment, the pre-emulsion composition is formulated suchthat dilution of at least 0.5 g or about 0.5 g, at least 1 g or about 1g, at least 2 g or about 2 g, at least 5 g or about 5 g, or at least 10g or about 10 g of the pre-emulsion composition into 8 or about 8 fluidounces of an aqueous medium; or dilution of the pre-emulsion compositionin an aqueous medium, at a dilution not more than 1:10 or about 1:10,not more than 1:25 or about 1:25, not more than 1:50 or about 1:50, notmore than 1:100 or about 1:100, not more than 1:250 or about 1:250 ornot more than 1:500, yields a liquid dilution composition that does notcontain visible particles, does not contain visible crystals, does notexhibit ringing and/or does not exhibit phase separation; and/or remainsfree from (or does not exhibit) visible particles, visible crystals,ringing and/or phase separation when stored at room temperature (e.g.25° C. or about 25° C.), or at a refrigerated temperature (e.g. 0-10° C.or about 0-10° C., e.g. at or about 4° C.), or at a frozen temperature(e.g. −20° C. or about −20° C.), wherein the storage is for at least oneday, at least one week, at least thirty days, or at least one year.

In one embodiment, the pre-emulsion composition is formulated such thatdilution of at least 0.5 g or about 0.5 g, at least 1 g or about 1 g, atleast 2 g or about 2 g, at least 5 g or about 5 g, or at least 10 g orabout 10 g of the pre-emulsion composition into 8 or about 8 fluidounces of a beverage; or dilution at not more than 1:10 or about 1:10,not more than 1:25 or about 1:25, not more than 1:50 or about 1:50, notmore than 1:100 or about 1:100, not more than 1:250 or about 1:250 ornot more than 1:500 into a beverage, yields a liquid dilutioncomposition that is at least as clear as, or substantially as clear as,the beverage, and/or remains as clear as, or substantially as clear as,the beverage when stored at room temperature (e.g. 25° C. or about 25°C.), or at a refrigerated temperature (e.g. 0-10° C. or about 0-10° C.,e.g. at or about 4° C.), or at a frozen temperature (e.g. −20° C. orabout −20° C.), wherein the storage is for at least one day, at leastone week, at least thirty days, or at least one year.

Also provided are liquid dilution compositions, which contain thepre-emulsion compositions diluted in an aqueous medium. Exemplary of theaqueous medium are beverages, such as, for example, water, juice, soda,tea, coffee, sports drinks, nutritional beverages, energy drinks, milk,and other beverages. The provided liquid dilution compositions areliquid dilution compositions containing any one or more of the providedpre-emulsion compositions. Typically, the provided liquid dilutioncompositions are compositions containing the pre-emulsion composition(s)and having any one or more of the properties of the desired liquiddilution compositions described above.

For example, in one embodiment, the provided liquid dilution compositioncontains a particle size less than 500 or about 500, less than 300 orabout 300, less than 200 or about 200 nm, less than 100 or about 100 nm,less than 50 or about 50 nm or less than 25 or about 25 nm, on theaverage or at the most. In another embodiment, the liquid dilutioncomposition has an NTU value less than 200 or about 200, less than 100or about 100, less than 50 or about 50, less than 25 or about 25, orless than 10 or about 10. In one example, the liquid dilutioncomposition does not contain visible particles, does not contain visiblecrystals, does not exhibit ringing and/or does not exhibit phaseseparation; and/or remains free from (or does not exhibit) visibleparticles, visible crystals, ringing and/or phase separation when storedat room temperature (e.g. 25° C. or about 25° C.), or at a refrigeratedtemperature (e.g. 0-10° C. or about 0-10° C., e.g. at or about 4° C.),or at a frozen temperature (e.g. −20° C. or about −20° C.), wherein thestorage is for at least one day, at least one week, at least thirtydays, or at least one year.

In one example, the aqueous medium contained in the liquid dilutioncomposition is a beverage, such as, for example, water, soda, milk, tea,coffee, juice, energy drink or a sports or nutrition beverage. In oneaspect, the liquid dilution composition is as clear or about as clear asthe beverage prior to addition of the pre-emulsion composition, and/orremains as clear or about as clear as the beverage when stored at roomtemperature (e.g. 25° C. or about 25° C.), or at a refrigeratedtemperature (e.g. 0-10° C. or about 0-10° C., e.g. at or about 4° C.),or at a frozen temperature (e.g. −20° C. or about −20° C.), wherein thestorage is for at least one day, at least one week, at least thirtydays, or at least one year.

In one embodiment, the dilution factor at which the pre-emulsioncomposition is diluted in the aqueous medium is not more than 1:10 orabout 1:10, not more than 1:25 or about 1:25, not more than 1:50 orabout 1:50, not more than 1:100 or about 1:100, not more than 1:250 orabout 1:250 or not more than 1:500. In another embodiment, theconcentrate is diluted in the aqueous medium to form the liquid dilutioncomposition at 0.5 g or about 0.5 g, at least 1 g or about 1 g, at least2 g or about 2 g, at least 5 g or about 5 g, or at least 10 g or about10 g of the concentrate into 8 or about 8 fluid ounces of the aqueousmedium. In another embodiment, the liquid dilution composition containsat least 25 mg or about 25 mg, at least 35 mg or about 35 mg, at least50 mg or about 50 mg or at least 100 mg or about 100 mg, at least 250 mgor about 250 mg, or at least 500 mg or about 500 mg of the non-polaractive ingredient per 8 fluid ounces of the liquid dilution composition.

In one embodiment, the liquid dilution composition does not containvisible particles; and/or remains free from visible particles whenstored at room temperature, or at a refrigerated temperature, or at afrozen temperature, wherein the storage is for at least one day, atleast one week, at least thirty days, or at least one year; and/or doesnot contain visible crystals, for example, remains free from visiblecrystals when stored at room temperature, or at refrigeratedtemperature, or at a frozen temperature, wherein the storage is for atleast one day, at least one week, at least thirty days, or at least oneyear; and/or does not exhibit ringing, for example, remains free fromringing when stored at room temperature, at a refrigerated temperature,or at a frozen temperature, wherein the storage is for at least one day,at least one week, at least thirty days, or at least one year; or doesnot exhibit phase separation, for example, does not exhibit phaseseparation when stored at room temperature, refrigerated temperature orfrozen temperature, wherein the storage is for at least one day, atleast one week, at least thirty days, or at least one year.

Also provided are methods for making the pre-emulsion compositions. Themethods can be used to produce any of the pre-emulsion compositionsprovided herein. In general, the methods for making the pre-emulsioncompositions are carried out by heating ingredients and mixing (e.g.homogenizing) the ingredients, and then cooling the mixed ingredients,whereby the mixture becomes waxy in consistency. In one example, themixture that is waxy in consistency is the pre-emulsion concentrate. Inanother example, additional steps can include adding one or more flavorsor other ingredients, to form the final pre-emulsion composition.

In one example of the methods, initial ingredients are mixed and heatedin a vessel; one or more additional ingredients are added to the vessel;the ingredients are homogenized, and the mixed ingredients are cooled,whereby the mixture becomes waxy in consistency, thereby generating thepre-emulsion composition.

In one embodiment, the initial ingredients include a surfactant, such asany of the surfactant of the provided pre-emulsion compositions asdescribed above, for example, a PEG-derivative of Vitamin E, such as aTPGD, e.g. a TPGS or a TPGS analog (such as a TPGS homolog); and the oneor more additional ingredients include a non-polar active ingredient,such as any of the non-polar active ingredient in any of thepre-emulsion concentrates provided herein.

In another embodiment, the initial ingredients include a non-polaractive ingredient, such as any of the non-polar active ingredient in anyof the pre-emulsion concentrates provided herein (e.g. aphytosterol-containing non-polar active ingredient); and the one or moreadditional ingredients include a surfactant, such as any of thesurfactant of the provided pre-emulsion compositions as described above,e.g. a PEG-derivative of Vitamin E, such as a TPGD, e.g. a TPGS or aTPGS analog (such as a TPGS homolog).

The amounts of the surfactant(s) and non-polar active ingredient(s) thatare added in the methods are selected based on the appropriateconcentration ranges of these ingredients in the final resultingpre-emulsion composition. For example, in one embodiment, the non-polaractive ingredient is added at an amount that is between 5% or about 5%and 15% or about 15%, by weight, of the pre-emulsion composition. Inanother embodiment, the non-polar active ingredient is added at anamount that is between 5% or about 5% and 35% or about 35%, by weight,of the pre-emulsion composition, or at any of the concentrations ofthese ingredients provided herein.

In one embodiment, the surfactant(s) is added at an amount that isbetween 40% or about 40% and 60% or about 60%, by weight, of thepre-emulsion composition. In another embodiment, the surfactant is addedat an amount that is between 65% or about 65% and 95% or about 95%, byweight, of the pre-emulsion composition, or any of the concentrations ofthe surfactant provided herein.

In one embodiment, the ingredients (e.g. the first ingredients, the oneor more additional ingredients or a combination thereof) further includea solvent that dissolves the non-polar active ingredient and differstherefrom. In one example, the amount of solvent is sufficient todissolve the non-polar active ingredient, for example, while heating theingredients. Exemplary solvents include solvents containing any one ormore of a Vitamin E oil, a flaxseed oil, a CLA and a safflower oil, or acombination thereof. In another embodiment, the ingredients furtherinclude one or more additional ingredients selected from among solvents,additional non-polar active ingredients, or combinations thereof, suchas, for example, Vitamin E oil, flaxseed oil, CLA and safflower oil.

In one example, the solvent, additional non-polar active ingredient(s)and/or combination thereof, is added at an amount that is between 1% orabout 1% and 6% or about 6% of the pre-emulsion composition. In anotherexample, the solvent is included at an amount that is between 1% orabout 1% and 15% or about 15%, for example, at or about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14 or 15%, by weight, of the pr-emulsioncomposition.

In another embodiment, the ingredients further comprise a co-surfactant,at an amount sufficient to stabilize the composition. In one example,the co-surfactant contains a phospholipid, such as a co-surfactantcontaining a phosphatidylcholine. In one aspect, the phospholipid isadded at an amount that is between 0.1% or about 0.1% and 1% or about1%, by weight, of the pre-emulsion composition.

In another embodiment, the ingredients further comprise at least onepreservative, such as benzyl alcohol or a preservative containing benzylalcohol. In one example, the preservative is added at an amountsufficient to preserve the composition, for example at an amount that isbetween 0.1% or about 0.1% and 1% or about 1%, by weight, of thecomposition.

In another embodiment, the ingredients further comprise an emulsionstabilizer. In one example, the emulsion stabilizer is added at anamount sufficient to stabilize the composition. In one example, theemulsion stabilizer comprises a blend of gums, such as a blend selectedfrom among any one or more of guar gum, xanthan gum and sodium alginate.

In another embodiment, one or more additional ingredients are addedafter mixing and heating the ingredients and/or after cooling orpartially cooling the ingredients. Exemplary of such additionalingredients are one or more flavors, for example, flavors added at anamount sufficient to enhance the taste of the composition, the smell ofthe composition, or a combination thereof. Exemplary flavors are lemonoil and/or D-limonene, or any of the flavors described herein. Otheradditional ingredients include, but are not limited to, pH adjusters,which typically are added at an amount sufficient to affect the pH ofthe composition, for example, a pH adjuster containing an acid or baseat an amount to affect the pH of the composition. Exemplary pH adjustersare compounds containing citric acid or phosphoric acid or a combinationthereof.

The mixing and heating steps can be carried out using any mixing andheating methods. In one example, the mixing is carried out with astandard mixer. In another example, the heating is carried out with aheating apparatus, such as, for example, a water-jacket, for example ona water-jacketed tank. In one embodiment, heating the ingredientscomprises heating the ingredients to 60° C. or about 60° C. In oneexample, the homogenizing is carried out with a reversible homogenizer.In one example, the homogenizing is carried out at between 850 or about850 rpm and 1200 or about 1200 rpm.

In one example, the methods for producing the pre-emulsion compositionsare carried out using a bench-top process, as described herein below. Inanother example, the methods are performed using a scaled-up process, asdescribed herein below. For example, the methods can be performed usinga scaled-up process such as the one illustrated in FIG. 1.

In this example, the initial ingredients are added and mixed in a mixingtank and mixed using a standard mixer, attached to the tank, forexample, mounted on the top of the tank. The ingredients are mixed andheated, typically to low heat (e.g. 60° C.), until dissolved, accordingto the provided methods. Once the initial ingredients are dissolved (byheating and mixing with the standard mixer) additional ingredient(s) areadded, and the mixture is homogenized. To begin the homogenization step,a homogenizer mounted on the mixing tank is turned on, for example, at850-1200 rpm. The additional ingredient(s) is added and the mixturehomogenized, typically while continuing to heat the mixture, e.g. whilemaintaining low heat. The homogenization is continued, with heating,until the ingredients dissolve. After the homogenization step, one ormore additional steps can be carried out. In one example (shown on theleft hand side), the ingredients are transferred, via transfer means toa packaging or holding tank. Typically, the pre-emulsion composition isfiltered using an end-product filter such as a 100 micron end-productfilter. The composition finally is transferred, for example, usingtransfer means, to a storage container. Typically, the composition istransferred into the storage container while it is still at a heatedtemperature, for example, between 48° C. or about 48° C. and 60° C. orabout 60° C. In this example, the composition then solidifies(developing a waxy consistency) while in the storage container. In otherexamples, the methods include variations of this exemplary scaled-upprocess using the provided methods, to make the pre-emulsioncompositions.

Also provided are methods of diluting the pre-emulsion compositions,e.g. in aqueous media such as beverages, to form the provided liquiddilution compositions. Exemplary of such methods are methods forproviding an oil-based additive, such as any one or more of thenon-polar active ingredients described herein. In one embodiment of themethods, one or more of the pre-emulsion compositions provided herein isadded to aqueous medium, for example, a beverage. In one example, thepre-emulsion composition is added to the aqueous medium (e.g. beverage)at an amount effective to deliver an effective amount of the additive(e.g. non-polar active ingredient).

In one embodiment of the methods the aqueous medium is heated, forexample, to at least 40° C. or at least about 40° C., for example, 41,42, 43, 44, 45, 46, 47, 48, 49, 50 or more ° C., for example, 48.9° C.(120° F. or about 120° F.), prior to, subsequent to, or simultaneouswith the addition of the pre-emulsion composition. In one such example,the pre-emulsion composition is added, at an appropriate dilution, asdescribed herein, to the heated aqueous medium, and mixed (e.g. stirred)until dispersed or dissolved in the solution. In one example, thepre-emulsion composition is heated before addition to the aqueousmedium, for example, to at least 40° C. or at least about 40° C., forexample, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more ° C., forexample, 48.9° C. (120° F. or about 120° F.). In another example, thepre-emulsion composition is added to the medium without heating.

In one embodiment, the methods further include cooling the resultingliquid dilution composition, for example, to room temperature, forexample, 25° C. or about 25° C.

In one embodiment, the methods further include packaging the aqueousliquid dilution composition, for example, by transferring to containers,such as vials or beverage containers. In one example, a portion of theliquid dilution composition is transferred to vials for analysis, forexample, evaluation of properties, such as clarity, turbidity, taste,smell, ringing, crystal formation and/or other properties.

Typically, the pre-emulsion composition is added to the medium, e.g.beverage, such that the medium contains an effective amount of theadditive (e.g. the non-polar active ingredient).

The effective amount of the additive, such as the non-polar activeingredient is the quantity and/or concentration of the additivenecessary for preventing, curing, ameliorating, arresting or partiallyarresting a symptom of a disease or disorder, or the quantity and/orconcentration desired by an individual for intake, such as daily intake,and/or nutritional supplementation, for example, an amount sufficient toenhance the nutritional, pharmaceutical, nutraceutical, health or energyproperty of a food, beverage, or other consumable. In some examples, thepre-emulsion composition is added to the aqueous medium such that theresulting liquid dilution composition contains an effective amount of aparticular non-polar compound, for example, a particular amount pervolume or weight of the composition, such as, for example, at least 25mg or about 25 mg, at least 35 mg or about 35 mg, at least 50 mg orabout 50 mg or at least 100 mg or about 100 mg, at least 250 mg or about250 mg, or at least 500 mg or about 500 mg of the non-polar activeingredient per 8 fluid ounces of the liquid dilution composition.

In one example, an effective amount is a concentration or amount of thepre-emulsion composition where at least 25 mg or about 25 mg, typicallyat least 35 mg, for example, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220,230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 425, 450,475, 500, 550, 600, 700, 800, 900, 1000, 1500, 2000 mg, or more, of thenon-polar active ingredient, is contained in at least 8 fluid ounces ofthe aqueous medium.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1

FIG. 1 sets forth a an exemplary scaled-up process 100 for carrying outthe provided methods for making the pre-emulsion compositions. In thisexample of the scaled-up process, the initial ingredients are added andmixed in a mixing tank 101 and mixed using a standard mixer 104, forexample, a LIGHTNIN® mixer (for example, model no. XJC117, a fixed-mountgear drive high-flow mixer), attached to the tank, for example, mountedon the top of the tank. The ingredients are mixed and heated, typicallyto low heat (e.g. 60° C.), until dissolved, according to the providedmethods. Once the initial ingredients are dissolved (by heating andmixing with the standard mixer) additional ingredient(s) are added, andthe mixture is homogenized. To begin the homogenization step, ahomogenizer 105 (e.g. an Arde Barinco, Inc. reversible homogenizer),mounted on the mixing tank, is turned on, for example, at 850-1200 rpm.The additional ingredient(s) is added and the mixture homogenized,typically while continuing to heat the mixture, e.g. while maintaininglow heat. The homogenization is continued, with heating, until theingredients dissolve. After the homogenization step, one or moreadditional steps can be carried out. In one example (shown on the lefthand side), the ingredients are transferred, via transfer means 102 to apackaging or holding tank 103. Typically, the pre-emulsion compositionis filtered using an end-product filter 106, such as a 100 micronend-product filter. As shown, the composition can be filtered directlyfrom the mixing tank 101 (as shown on the right), or it can be filteredafter transfer to the packaging/holding tank 103 (as shown on the left).The composition finally is transferred, for example, using transfermeans 102, to a storage container 107. Typically, the composition istransferred into the storage container while it is still at a heatedtemperature, for example, between 48° C. or about 48° C. and 60° C. orabout 60° C. In this example, the composition then solidifies(developing a waxy consistency) while in the storage container.Variations of this exemplary scaled-up process (FIG. 1) also can becarried out using the provided methods, to make the pre-emulsioncompositions.

DETAILED DESCRIPTION A. DEFINITIONS 23 B. COMPOSITIONS CONTAININGNON-POLAR COMPOUNDS 55 1. Pre-emulsion compositions containing thenon-polar compounds 58 a. Formulating the pre-emulsion compositions 60i. Common ingredients and typical concentration ranges 63 ii. Evaluationof the initial pre-emulsion composition 65 (1) Clarity 66 (2) Empiricalevaluation 68 (3) Particle size 69 (4) Turbidity measurement 70 iii.Selecting a formulation and modifying formulations 71 b. Non-PolarCompounds 73 i. Polyunsaturated Fatty Acid (PUFA)-containing activeingredients 75 (1) Omega-3 fatty acid compounds 78 (a) DHA/EPA 78 (i)Fish Oils 79 (ii) Algae oil 81 (b) Flax Seed Oil - omega 3 (ALA) 82 (2)Omega-6 compounds 82 (a) Borage oil (Gamma-Linolenic 83 Acid (GLA)) (3)Saw Palmetto extract 83 (4) Conjugated Linoleic Acid (CLA) 84 ii.Coenzyme Q Active Ingredients 85 (1) Coenzyme Q10 85 iii.Phytosterol-Containing Active Ingredients 86 c. Other components of thepre-emulsion compositions 87 i. Surfactants 87 ii. PEG-Derivatives ofVitamin E 88 (1) Tocopherols and Tocotrienols 89 (2) PEG moieties 90 (3)Linkers 90 (4) Tocopherol polyethylene glycol and Tocotrienol 91polyethylene glycol diesters (dicarboxylic acid esters of Vitamin Elinked to PEG) (5) Other Vitamin E PEG Esters 92 (a) TPGS Surfactants 93iii. Concentration of the surfactant 94 iv. HLB 95 (1) TPGS 96 (2)Co-surfactants (emulsifiers) 97 (a) Phospholipids 97 v. Preservativesand Sterilizers 98 vi. Emulsion stabilizers (co-emulsifier) 98 vii.Solvents 99 viii. Flavors 100 ix. pH adjusters 101 2. Powder 101 3.Liquid dilution compositions containing the 105 diluted pre-emulsioncompositions a. Clarity 107 i. Clarity determined by empiricalevaluation 108 ii. Clarity determined by particle size or number ofparticles 108 iii. Turbidity 109 b. Stability 110 c. Desirablecharacteristics for human consumption 111 d. Safety 112 e. Oralbioavailability 112 C. METHODS FOR MAKING PRE-EMULSION COMPOSITIONS 112CONTAINING NON-POLAR COMPOUNDS 1. Equipment for making the pre-emulsioncompositions 113 a. Scales 113 b. Purifiers, including filters 113 c.Vessels for mixing the ingredients 114 d. Mixers 115 e. Heatingapparatuses 117 f. Cooling apparatuses 118 g. Transfer means 119 h.Evaluation equipment 119 2. General methods for making the pre-emulsioncompositions 120 a. Combining the ingredients 121 i. Weighing theingredients 121 ii. Dissolving first ingredient(s) - standard mixer 121iii. Homogenizing the mixture 122 iv. Ingredients and order of addition123 b. Additional steps 124 i. Additional ingredients 124 ii. Evaluationof the pre-emulsion composition 125 iii. Filtering 125 iv. Transferand/or packaging 125 3. Bench-top process 126 4. Scaled-up manufacturingprocess 127 a. Combining the ingredients 128 i. Dissolving the initialingredients - standard mixing 128 ii. Addition of the non-polar compoundand homogenizing 128 b. Additional steps 129 D. METHODS FOR MAKING THELIQUID DILUTION COMPOSITIONS 129 CONTAINING THE DILUTED PRE-EMULSIONCOMPOSITIONS 1. Dilutions 131 2. Analyzing the aqueous liquid dilutioncompositions 132 containing the liquid pre-emulsion compositions a.Clarity/turbidity 132 i. Empirical evaluation 133 ii. Particle size 133iii. Turbidity measurement 134 E. EXAMPLES 134

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the invention(s) belong. All patents, patent applications,published applications and publications, GENBANK sequences, websites andother published materials referred to throughout the entire disclosureherein, unless noted otherwise, are incorporated by reference in theirentirety. In the event that there is a plurality of definitions forterms herein, those in this section prevail. Where reference is made toa URL or other such identifier or address, it is understood that suchidentifiers can change and particular information on the internet cancome and go, but equivalent information is known and can be readilyaccessed, such as by searching the internet and/or appropriatedatabases. Reference thereto evidences the availability and publicdissemination of such information.

As used herein, colloid refers to a mixture containing two phases, adispersed phase and a continuous phase, the dispersed phase containingparticles (droplets) distributed throughout the continuous phase.Colloidal mixtures include aerosols, foams and dispersions, for example,emulsions, for example, nanoemulsions. A liquid colloid, for example, ananoemulsion, can have a similar appearance, for example, clarity, to asolution, in which there is no dispersed phase.

As used herein, emulsion refers to a colloidal dispersion of twoimmiscible liquids, for example, an oil and water (or other aqueousliquid), one of which is part of a continuous phase and the other ofwhich is part of a dispersed phase. The provided compositions includeemulsions, typically oil-in-water nanoemulsions, in which the oil phaseis the dispersed phase and the water phase is the continuous phase.Emulsions typically are stabilized by one or more surfactants and/orco-surfactants and/or emulsion stabilizers. Surfactants form aninterfacial film between the oil and water phase of the emulsion,providing stability. Typically, the nanoemulsions of the providedcompositions contain micelles, containing one or more surfactantsurrounding a non-polar active ingredient, which are dispersed in thewater phase. Exemplary of the provided emulsions are liquid dispersioncompositions, which are made by diluting the provided pre-emulsioncompositions.

As used herein, a nanoemulsion is an emulsion in which the disperseddroplets, for example, the micelles, have a diameter (particle size)less than 1000 nm or less than about 1000 nm, typically, less than 500nm or less than about 500 nm, typically less than 300 or about 300 nm,for example, less than 250 nm or about 250 nm, for example, less than200 nm or less than about 200 nm, for example, less than or less thanabout 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,150, 160, 170, 180, 190, or 200 nm. Exemplary of nanoemulsions are theprovided liquid dilution compositions, for example, the aqueous liquiddilution compositions, containing the diluted pre-emulsion compositions.

As used herein, “surfactant” and “surface active agent” are usedsynonymously to refer to synthetic and naturally occurring amphiphilicmolecules, for example, molecules having both hydrophobic portion(s) andhydrophilic portion(s). In one example, the hydrophobic portion of thesurfactant molecule is a hydrophobic tail and the hydrophilic portion ofthe surfactant is a hydrophilic head. Due to their amphiphilic(amphipathic) nature, surfactants and co-surfactants typically canreduce the surface tension between two immiscible liquids, for example,the oil and water phases in an emulsion, for example, a nanoemulsion,thus stabilizing the emulsion. Different surfactants can characterizedbased on their relative hydrophobicity and/or hydrophilicity. Forexample, relatively lipophilic surfactants are more soluble in fats,oils and waxes, typically having HLB values less than 10 or about 10,while relatively hydrophilic surfactants are more soluble in aqueouscompositions, for example, water, and typically have HLB values greaterthan 10 or about 10. Relatively amphiphilic surfactants are soluble inboth oil and water based liquids and typically have HLB values close to10 or about 10.

Typically, the surfactants used in the provided compositions have an HLBvalue between 14 or about 14 and 20 or about 20, for example, 14, 15,16, 17, 18, 19, 20, about 14, about 15, about 16, about 17, about 18,about 19 or about 20. Exemplary of a surfactant that can be used in theprovided compositions is a PEG-derivative of Vitamin E, such astocotrienol or tocopherol PEG diesters, such as TPGS (e.g. TPGS 1000)and TPGS analogs. Other known surfactants having HLB values between 14or about 14 and 20 or about 20, typically between about 16 and 18, alsocan be suitable. For example, surfactants having similar properties toTPGS also can be used. Typically, the surfactant is a naturalsurfactant, for example, a surfactant that is G.R.A.S. (generallyrecognized as safe) by the FDA and/or Kosher certified.

Surfactants include, but are not limited to, soaps, detergents, lipids,emulsifiers, dispersing agents and wetting agents. Surfactants includemolecules that emulsify liquids, for example, by forming an emulsion inan aqueous medium or aqueous liquid dilution composition, for example,forming a colloidal dispersion of two immiscible liquids in the form ofdroplets, for example, an emulsion such as a microemulsion. Surfactantsinclude compounds that form various macromolecular structures, forexample, aggregates, in liquids, for example, micelles, lipid bilayerstructures, including liposomes, and inverse micelles. The compositions(e.g. nanoemulsions) provided herein typically contain micelles, forexample, micelles encapsulating the non-polar active ingredient(s).

As used herein, “pre-emulsion composition” refers to the providedcompositions containing the non-polar compounds that can be diluted inaqueous medium to form the liquid dilution compositions, typicallyaqueous liquid dilution compositions. In one example, the aqueous liquiddilution composition are clear aqueous liquid dilution compositions.Typically, the pre-emulsion compositions are solid compositions.Typically, the pre-emulsion compositions are non-aqueous pre-emulsioncompositions. Typically, the pre-emulsion composition is formulated,(e.g. using the provided methods for formulating the pre-emulsioncompositions) such that dilution of the composition in an aqueous mediumyields an aqueous liquid dilution composition having one or moredesirable properties, for example, being free from visible particlesand/or visible crystals, exhibiting no ringing or phase separation,and/or having a desirable clarity, for example, a desired turbidity(NTU) value (e.g. an NTU of less than 1000 or about 1000, typically lessthan 500 or about 500, typically less than 300 or about 300 nm,typically less than 250 or about 250 typically less than 200 or about200, e.g. less than 150 or about 150) or a desired average particle size(e.g. less than 1000 or about 1000, typically less than 500 or about500, typically less than 300 or about 300 nm, typically less than 200 orabout 200, for example, a particle size equal to, less than or less thanabout 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,150, 160, 170, 180, 190, or 200 nm). In another example, thepre-emulsion composition is formulated such that dilution of thecomposition in an aqueous medium, for example, a beverage, yields aliquid dilution composition that is as clear as or substantially asclear as the aqueous medium itself. The provided pre-emulsioncompositions contain one or more non-polar active ingredients and atleast one surfactant. Typically, the pre-emulsion compositions furthercontain a preservative, for example, a natural preservative such asbenzyl alcohol. In some examples, the pre-emulsion compositions furthercontain one or more solvents, such as oils, for example, Vitamin E oiland/or flaxseed oil.

As used herein, a solid pre-emulsion composition is a pre-emulsioncomposition that is not a liquid (or gas) at room temperature (e.g.ambient temperature, for example, 25° C. or about 25° C.), for example,having a waxy consistency at room temperature (ambient temperature), forexample at 25° C. or about 25° C. Typically, the solid pre-emulsioncompositions become liquid when heated, for example, when heated to 120°F., or about 120° F., to 125° F., or about 125° F., to 140° F., or about140° F., 50° C. or about 50° C., 60° C. or about 60° C. Typically, thesolid pre-emulsion compositions are non-aqueous compositions.

As used herein, a PEG derivative of Vitamin E is a compound containingone or more Vitamin E moiety (e.g. a tocopherol or tocotrienol) joined,for example by an ester, ether, amide or thioester bond, with one ormore polyethylene glycol (PEG) moieties, via a linker, for example adicarboxylic or tricarboxylic acid. Exemplary of PEG derivatives ofVitamin E are tocopherol polyethylene glycol succinate (TPGS), TPGSanalogs, TPGS homologs and TPGS derivatives.

As used herein, a tocopherol polyethylene glycol diester (TPGD) is aPEG-derivative of tocopherol where the linker is a dicarboxylic acid (acarboxylic acid having two carboxy groups, e.g. succinic acid), such assuccinic acid. Exemplary of dicarboxylic acids that can be used aslinkers in these tocopherol and tocotrienol PEG diester surfactants aresuccinic acid, sebacic acid, dodecanodioic acid, suberic acid, orazelaic acid, citraconic acid, methylcitraconic acid, itaconic acid,maleic acid, glutaric acid, glutaconic acid, fumaric acids and phthalicacids. Exemplary of TPGDs are tocopherol succinate polyethylene glycol(TPGS), tocopherol sebacate polyethylene glycol, tocopheroldodecanodioate polyethylene glycol, tocopherol suberate polyethyleneglycol, tocopherol azelaate polyethylene glycol, tocopherol citraconatepolyethylene glycol, tocopherol methylcitraconate polyethylene glycol,tocopherol itaconate polyethylene glycol, tocopherol maleatepolyethylene glycol, tocopherol glutarate polyethylene glycol,tocopherol glutaconate polyethylene glycol, and tocopherol phthalatepolyethylene glycol, among others.

As used herein, “tocopherol polyethylene glycol succinate,” “TPGS,”“tocopheryl polyethylene glycol succinate surfactant” and “TPGSsurfactant” refer to tocopherol polyethylene glycol (PEG) diesters thatare formed by joining, via esterification, tocopherol succinate, whichitself is an ester made by esterification of tocopherol and succinicacid. The PEG moiety of the TPGS surfactant can be any PEG moiety, forexample, PEG moieties between 200 or about 200 and 20,000 or about20,000 Da, typically between 200 or about 200 and 6000 or about 6000 Da,for example, between 600 or about 600 Da and 6000 or about 6000 Da,typically between 200 or about 200 Da and 2000 or about 2000 Da, between600 or about 600 Da and 1500 or about 1500 Da, 200 or about 200 Da, 300or about 300 Da, 400 or about 400 Da, 500 or about 500 Da, 600 or about600 Da, 800 or about 800 Da, and 1000 or about 1000 Da, and PEG moietiesthat are modified, for example, methylated PEG (m-PEG) and/or PEGmoieties including other PEG analogs, e.g. PEG-NHS, PEG-aldehyde,PEG-SH, PEG-NH₂, PEG-CO₂H, and branched PEGs.

Exemplary of the TPGS surfactants is TPGS-1000, which has a PEG moietyof 1000 Da. The TPGS can be any natural, water-soluble, tocopherolpolyethylene glycol succinate, for example, the food grade TPGS soldunder the name Eastman Vitamin E TPGS®, food grade, by Eastman ChemicalCompany, Kingsport, TN. This TPGS is a water-soluble form ofnatural-source vitamin E, which is prepared by esterifying the carboxylgroup of crystalline d-alpha-tocopheryl acid succinate with polyethyleneglycol 1000 (PEG 1000), and contains between 260 and 300 mg/g totaltocopherol. A similar compound can be made by esterifying the carboxylgroup of the d,1 form of synthetic Vitamin E with PEG 1000. It forms aclear liquid when dissolved 20% in water. This tocopheryl polyethyleneglycol is a water-soluble preparation of a fat-soluble vitamin (vitaminE), for example, as disclosed in U.S. Pat. Nos. 3,102,078 and 2,680,749and U.S. Published Application Nos. 2007/0184117 and 2007/0141203. Alsoexemplary of the TPGS surfactant that can be used in the providedcompositions is the Water Soluble Natural Vitamin E (TPGS), sold byZMC-USA, The Woodlands, Texas. Any known source of TPGS can be used.Typically, the TPGS surfactant is GRAS and Kosher certified. TPGStypically has an HLB value of between 16 or about 16 and 18 or about 18.

As used herein, analog refers to a chemical compound that isstructurally similar to another compound (referred to as a parentcompound), but differs slightly in composition, for example, by thevariation, addition or removal of an atom, one or more units (e.g.methylene unit(s)- (CH₂)_(n)) or one or more functional groups. Theanalog can have different chemical or physical properties compared withthe original compound and/or can have improved biological and/orchemical activity. Alternatively, the analog can have similar oridentical chemical or physical properties compared with the originalcompound and/or can have similar or identical biological and/or chemicalactivity For example, the analog can be more hydrophilic or it can havealtered reactivity as compared to the parent compound. The analog canmimic the chemical and/or biologically activity of the parent compound(i.e., it can have similar or identical activity), or, in some cases,can have increased or decreased activity. The analog can be a naturallyor non-naturally occurring (e.g. synthetic) variant of the originalcompound. Other types of analogs include isomers (enantiomers,diasteromers, and the like) and other types of chiral variants of acompound, as well as structural isomers. The analog can be a branched orcyclic variant of a linear compound. For example, a linear compound canhave an analog that is branched or otherwise substituted to impartcertain desirable properties (e.g., improve hydrophilicity orbioavailability). Exemplary of the analogs used in the providedcompositions and methods are TPGS analogs, which typically are used assurfactants, for example, in place of the TPGS parent compound in any ofthe provided compositions.

As used herein, homolog refers to an analog that differs from the parentcompound only by the presence or absence of a simple unit, such as amethylene unit, or some multiple of such units, e.g., —(CH₂)_(n)—.Typically, a homolog has similar chemical and physical properties as theparent compound. Exemplary of the homologs used in the providedcompositions and methods are TPGS homologs.

As used herein, “tocopherol polyethylene glycol succinate analog” “TPGSanalog” and “TPGS analog surfactant” refer to compounds, other thanTPGS, that are similar to a parent TPGS compound, but differ slightly incomposition, for example, by the variation, addition or removal of anatom, one or more units (e.g. methylene unit(s)- (CH₂)_(n)) or one ormore functional groups. TPGS analogs include Vitamin E derivedsurfactants, including PEG derivatives of Vitamin E, including vitamin EPEG diesters, such as, but not limited to, tocophyrol polyethyleneglycol sebacate (PTS), tocopherol polyethylene glycol dodecanodioate(PTD), tocopherol polyethylene glycol suberate (PTSr), tocopherolpolyethylene glycol azelaate (PTAz) and polyoxyethanyl tocotrienylsebacate (PTrienS) as well as other PEG derivatives of Vitamin E. In oneexample, the surfactant in the provided compositions is a TPGS analog.

Exemplary of TPGS analogs are compounds, other than TPGS compounds,having the formula shown in Scheme I.

where R¹, R², R³ and R⁴ each independently is H or Me; each dashed lineis, independently, a single or double bond; n is an integer from 1-5000;m and q each independently are 0 or 1; and p is an integer from 1-20.

For example, TPGS analogs include compounds having the formula in SchemeI, where, when the bonds represented by the dashed lines marked by “A”and “B” are single bonds, m and q both equal 0, and p is any integerfrom 2-20. TPGS analogs also include compounds where the dashed line atB or the dashed line at A, or both the dashed lines, represents at leastone double bond. For example, TPGS analogs include a compound as inScheme I, where when the dashed line in A represents only single bonds,the dashed line in “B” represents one or more double bond, e.g.tocotrienol PEG diesters. TPGS also include compounds as in Scheme I,where when the dashed line marked “B” represents only single bonds, thedashed line marked “A” represents one or more double bonds; or when thedashed line labeled “A” does not represent double bonds, and m and q areboth zero, p is greater than 1. For example, TPGS analogs includecompounds where one or more of the dashed lines represents a doublebond, for example, PEG derivatives of tocotrienol esters (e.g. PTrienS).

Also exemplary of TPGS analogs include compounds other than TPGS havingthe formula shown in SCHEME III:

where R¹, R², R³ and R⁴ are hydrogen or methyl (CH₂), and n is aninteger selected from among 1-5000.

As used herein, TPGS-1000 analogs are compounds other than TPGS-1000that are similar to a parent TPGS-1000 compound, but differ slightly incomposition, for example, by the variation, addition or removal of anatom, one or more units (e.g. methylene unit(s)-(CH₂)_(n)) or one ormore functional groups. In one example, the surfactant in thecompositions provided herein is a TPGS-1000 analog. Suitable TPGS-1000analogs include, but are not limited to, other TPGS compounds, havingPEG moietie(s) that vary in chain length and molecular weight comparedto TPGS-1000, including, for example, TPGS compounds having PEG moietiesbetween 200 or about 200 to 20,000 or about 20,000 Da, typically between200 and 6000 Da, for example, between 600 or about 600 Da and 6000 orabout 6000 Da, typically between 200 or about 200 Da and 2000 or about2000 Da, between 600 or about 600 Da and 1500 or about 1500 Da 200, 300,400, 500, 600, 800, and 1000 Da. Also exemplary of TPGS-1000 analogs areTPGS compounds having PEG moieties that are modified, for example,methylated PEG (m-PEG) and/or PEG moieties including other PEG analogs,e.g. PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH₂, PEG-CO₂H, and branchedPEGs. Also exemplary of TPGS-1000 analogs are any TPGS analogs, e.g.Vitamin E derived surfactants, including PEG derivatives of Vitamin E,including vitamin E PEG diesters, such as, but not limited to,tocopherol polyethylene glycol sebacate (PTS), tocopherol polyethyleneglycol dodecanodioate (PTD), tocopherol polyethylene glycol suberate(PTSr), tocopherol polyethylene glycol azelaate (PTAz) andpolyoxyethanyl tocotrienyl sebacate (PTrienS) as well as other PEGderivatives of Vitamin E.

As used herein, TPGS homologs are analogs of TPGS that differ from aTPGS parent compound only by the presence or absence of a simple unit,such as a methylene unit, or some multiple of such units, e.g.,—(CH₂)_(n)—. In one aspect, TPGS homologs are used as surfactants in theprovided compositions. Typically, suitable TPGS homologs have similarsurfactant properties compared to the parent compound (TPGS), forexample, similar HLB values, for example, HLB values between 14 or about14 and 20 or about 20. Exemplary of TPGS homologs are tocophyrolpolyethylene glycol sebacate (PTS), tocopherol polyethylene glycoldodecanodioate (PTD), tocopherol polyethylene glycol suberate (PTSr),tocopherol polyethylene glycol azelaate (PTAz). Exemplary of TPGShomologs are compounds having the formula in Scheme I (above), whereneither the A or B dashed line represents a double bond and where, whenm and q both are 0, p is greater than 1.

As used herein, TPGS-1000 homologs are analogs of TPGS-1000 that differfrom a TPGS-1000 parent compound only by the presence or absence of asimple unit, such as a methylene unit, or some multiple of such units,e.g., —(CH₂)_(n)—. Suitable TPGS-1000 homologs have similar surfactantproperties compared to the parent compound (TPGS-1000), for example,similar HLB values, for example, HLB values between 14 or about 14 and20 or about 20. Suitable TPGS-1000 homologs include TPGS-1000 homologswith slight variations in the length of the PEG chain moiety, andme-TPGS-1000, which is a TPGS-1000 having a methyl cap on the PEGmoiety.

As used herein, HLB refers to a value that is used to index and describea surfactant according to its relative hydrophobicity/hydrophilicity,relative to other surfactants. A surfactant's HLB value is an indicationof the molecular balance of the hydrophilic and lipophilic portions ofthe surfactant, which is an amphipathic molecule. Each surfactant andmixture of surfactants (and/or co-surfactants) has an HLB value that isa numerical representation of the relative weight percent of hydrophobicand hydrophilic portions of the surfactant molecule(s). HLB values arederived from a semi-empirical formula. The relative weight percentagesof the hydrophobic and hydrophilic groups are indicative of surfactantproperties, including the molecular structure, for example, the types ofaggregates the surfactant will form and the solubility of thesurfactant. See, for example, Griffin, W.C. J. Soc. Cos. Chem. 1:311(1949).

Surfactant HLB values range from 1-45, while the range for non-ionicsurfactants typically is from 1-20. The more lipophilic a surfactant is,the lower its HLB value. Conversely, the more hydrophilic a surfactantis, the higher its HLB value. Lipophillic surfactants have greatersolubility in oil and lipophilic substances, while hydrophilicsurfactants dissolve more easily in aqueous media. In general,surfactants with HLB values greater than 10 or greater than about 10 arecalled “hydrophilic surfactants,” while surfactants having HLB valuesless than 10 or less than about 10 are referred to as “hydrophobicsurfactants.” HLB values have been determined and are available for aplurality of surfactants (e.g. see U.S. Pat. No. 6,267,985). It shouldbe appreciated that HLB values for a given surfactant or co-surfactantcan vary, depending upon the empirical method used to determine thevalue. Thus, HLB values of surfactants and co-surfactants provide arough guide for formulating compositions based on relativehydrophobicity/hydrophilicity. For example, a surfactant typically isselected from among surfactants having HLB values within a particularrange of the surfactant or co-surfactant, that can be used to guideformulations. Table 1 lists HLB values of exemplary surfactants andco-surfactants.

TABLE 1 HLB Values of Exemplary Surfactants and Co-SurfactantsSurfactant/co-surfactant HLB PEG-2 Hydrogenated Castor Oil 1.7 SorbitanTrioleate 1.8 Sorbitan Tristearate 2.1 Glyceryl Stearate 3.5 SorbitanSesquioleate 3.7 Labrafil 4 Sorbitan Oleate 4.3 Sorbitan monostearate4.7 PEG-2 oleyl ether 4.9 PEG-2 stearyl ether 4.9 PEG-7 HydrogenatedCastor Oil 5 PEG-2 cetyl ether 5.3 PEG-4 Sorbitan Stearate 5.5 PEG-2Sorbitan Isostearate 6 Sorbitan Palmitate 6.7 Triton SP-135 8 Sorbitanmonolaurate 8.6 PEG-40 Sorbitan Peroleate 9.5 PEG-4 lauryl ether 9.7Polysorbate 81 10 PEG-40 Sorbitan Hexaoleate 10 PEG-40 SorbitanPerisostearate 10 PEG-10 Olive Glycerides 10 PEG sorbitol hexaoleate10.2 Polysorbate 65 10.5 PEG-25 Hydrogenated Castor Oil 10.8 Polysorbate85 11 PEG-7 Glyceryl Cocoate 11 PEG-8 Stearate 11.1 PEG sorbitantetraoleate 11.4 PEG-15 Glyceryl Isostearate 12 PEG-35 Almond Glycerides12 Tocopherol polyethylene glycol succinate (TPGS) 16-18 PEG-10 oleylether 12.4 PEG-8 isooctylphenyl ether 12.4 PEG-10 stearyl ether 12.4PEG-35 Castor Oil 12.5 PEG-10 cetyl ether 12.9 Nonoxynol-9 12.9 PEG-40Castor Oil 13 PEG-10 isooctylphenyl ether 13.5 PEG-40 HydrogenatedCastor Oil 14 Labrasol 14 Nonoxynol-15 14.2 PEG-12 tridecyl ether 14.5PEG-18 tridecyl ether 14.5 Polysorbate 60 14.9 Polysorbate 80 15 PEG-20Glyceryl Stearate 15 PEG-20 Stearate 15 PEG-20 stearyl ether 15.3 PEG-20oleyl ether 15.3 Polysorbate 40 15.6 PEG20 cetyl ether 15.7 PEG(20)hexadecyl ether 15.7 PEG-60 Hydrogenated Castor Oil 16 PEG-30 Stearate16.5 Polysorbate 20 16.7 PEG-75 Lanolin 16.7 PEG23 lauryl ether 16.9PEG-40 Stearate 17.3 PEG-50 Stearate 17.7 PEG40 isooctylphenyl ether17.9 PEG-100 Stearate 18.8 Pluronic F68 29 Phosphatidylcholine 7.6

The surfactants and HLB values set forth in Table 1 are exemplary. Anyknown surfactant or co-surfactant can be used with the providedcompositions (e.g. see U.S. Pat. No. 6,267,985). The surfactant(s)contained in the provided compositions typically have an HLB valuebetween 14 or about 14 and 20 or about 20, for example, 14, 15, 16, 17,18, 19, 20, about 14, about 15, about 16, about 17, about 18, about 19or about 20. Exemplary of a surfactant that can be used in the providedcompositions is a PEG-derivative of Vitamin E, such as tocotrienol ortocopherol PEG diesters, such as TPGS (e.g. TPGS 1000) and TPGS analogs.Other known surfactants having HLB values between 14 or about 14 and 20or about 20, typically between about 16 and 18, also can be suitable.For example, surfactants having similar properties to TPGS also can beused. Typically, the surfactant is a natural surfactant, for example, asurfactant that is G.R.A.S. (generally recognized as safe) by the FDAand/or Kosher certified.

As used herein, micelle refers to aggregates formed by surfactants thattypically form when the surfactant is present in an aqueous composition,typically when the surfactant is used at a concentration above thecritical micelle concentration (CMC). In micelles, the hydrophilicportions of the surfactant molecules contact the aqueous or the waterphase, while the hydrophobic portions form the core of the micelle,which can encapsulate non-polar ingredient(s), for example, thenon-polar compounds in the provided compositions. Typically, thesurfactants in the provided aqueous dilution compositions form micellescontaining the non-polar ingredient at their center in aqueous liquiddilution compositions. Typically, the micelles in the provided aqueousdilution compositions have a particle size of less than about 1000 nm,typically, less than 500 nm or less than about 500 nm, typically lessthan 300 or about 300 nm, for example, less than 250 nm or about 250 nm,for example, less than 200 nm or less than about 200 nm, for example,less than or less than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100,110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 nm.

As used herein, inverse micelles are surfactant aggregates thattypically form in lipophilic solution, with the hydrophilic portionsforming the core. When the cross sectional area of the hydrophobicregion of the surfactant molecule is greater than that of thehydrophilic part of the molecule, the formation of micelles, which canbe hexagonal phase structures, is favored.

As used herein, liposomes are surfactant aggregates composed of lipidbilayers, typically having an aqueous core. Liposomes typically areformed by lipid surfactants, typically, phospholipids, which areamphipathic, phosphate-containing lipids, for example, moleculescontaining one phosphate, a glycerol and one or more fatty acids, andsimilar surfactants. Alternatively, phospholipid surfactants can be usedas co-surfactants, which can be incorporated into aggregates of othersurfactant(s), for example, micelles. Lipid bilayers are two dimensionalsheets in which all of the hydrophobic portions, e.g., acyl side chains,are shielded from interaction with aqueous liquid, except those at theends of the sheet. An energetically unfavorable interaction of the acylchains with water results in the folding of the bilayers to formliposomes, three-dimensional lipid bilayer vesicles. In one example, theliposome is formed as a single bilayer enclosing a single aqueous space(small unilamellar vesicles; SUVS). In another example, the liposome iscomposed of concentric bilayers with many aqueous spaces alternatingwith the bilayers (multilamellar vesicles; MLVS). Liposomes can be usedto encapsulate both hydrophobic and hydrophilic active ingredients. Inliposomes, non-polar active ingredients typically are partitioned withinthe bilayers whereas hydrophilic active ingredients typically aretrapped within the aqueous compartments. In one example, liposomes canbe advantages as a carrier/encapsulation system because they are stableand can protect the active ingredients from degradation, e.g., byoxygen, digestive enzymes, etc.

As used herein, “co-surfactant” is used to refer to a surfactant,typically a phospholipid, that is used, in the provided compositions, incombination with a surfactant, for example, a primary surfactant, forexample, to improve the emulsification of the provided compositionsand/or compounds, for example, to emulsify the ingredients. In oneexample, the provided compositions contain at least one surfactant andat least one co-surfactant. Typically, the co-surfactant is a lipid, forexample, a phospholipid, for example, phosphatidylcholine. In oneexample, the co-surfactant has an HLB value of between 7 or about 7 and8 or about 8. Typically, the co-surfactant represents a lower percent,by weight, of the provided compositions, compared to the surfactant.Thus, the provided compositions typically have a lower concentration ofthe co-surfactant(s) than of the surfactant.

As used herein, a phospholipid is an amphipathic, phosphate-containinglipid, for example, a molecule containing one phosphate, a glycerol andone or more fatty acids. In one example, one or more phospholipids isused as a co-surfactant in the provided compositions. Exemplary of thephospholipids used in the provided compositions are lecithin, includingphosphatidylcholine (PC), phosphatidylethanolamine (PE),distearoylphosphatidylcholine (DSPC), phosphatidylserine (PS),phosphatidtylglycerol (PG), phosphatidic acid (PA), phosphatidylinositol(PI), sphingomyelin (SPM) or a combination thereof. Typically, thephospholipid is phosphatidylcholine (PC), which sometimes is referred toby the general name “lecithin.” Exemplary of the phospholipids that canbe used as co-surfactants in the provided compositions are thephospholipids sold by Lipoid, LLC, Newark, N.J., for example, PurifiedEgg Lecithins, Purified Soybean Lecithins, Hydrogenated Egg and SoybeanLecithins, Egg Phospholipids, Soybean Phospholipids, Hydrogenated Eggand Soybean Phospholipids. Synthetic Phospholipids, PEG-ylatedPhospholipids and phospholipid blends sold by Lipoid, LLC. Exemplary ofthe phosphatidylcholine that can be used as a co-surfactant in theprovided compositions is the phosphatidylcholine composition sold byLipoid, LLC, under the name Lipoid S100, which is derived from soyextract and contains greater than 95% or greater than about 95%phosphatidylcholine.

Typically, for micelle formation, surfactant(s) are used in which thecross sectional area of the hydrophilic portion of the surfactantmolecule is greater than that of the hydrophobic portion of themolecule. For example, TPGS is a surfactant used to stabilizeoil-in-water emulsions containing the non-polar active ingredients, forexample, in nanometer-sized droplets suspended or dispersed in anaqueous phase or aqueous liquid, for example, aqueous medium, asspherical micelles, containing the hydrophilic portions of themolecule(s) facing the aqueous phase and the hydrophobic portions at thecenter of the spherical micelles, for example, surrounding the non-polaractive ingredient.

When the cross sectional area of the hydrophobic region of thesurfactant molecule is greater than that of the hydrophilic part of themolecule, the formation of hexagonal phase structures, sometimesreferred to as an inverse micelle is favored.

Typically, in the provided emulsion compositions, the surfactants and/orco-surfactants, aggregate in the nanoemulsions and the aqueous liquidsto form micelles, which contain the non-polar compound(s). Thehydrophilic portion(s) of the surfactant molecules are oriented towardthe outside of the micelle, in contact with the aqueous medium, whilethe hydrophobic portion(s) of the surfactant molecules are orientedtoward the center of the micelle, in contact with the non-polarcompound(s), which is contained in the center of the micelle. Themicelles can contain more than one surfactant.

As used herein, “tocopherol polyethylene glycol succinate surfactant”and “TPGS surfactant” are used synonymously to refer to any natural,water-soluble, tocopherol polyethylene glycol succinate surfactant ortocopheryl polyethylene glycol surfactant, for example, the food gradeTPGS surfactant sold under the name Eastman Vitamin E TPGS®, food grade,by Eastman Chemical Company, Kingsport, TN. This surfactant is awater-soluble form of natural-source vitamin E, which is prepared byesterifying the carboxyl group of crystalline d-alpha-tocopheryl acidsuccinate with polyethylene glycol 1000 (PEG 1000), and contains between260 and 300 mg/g total tocopherol. A similar compound can be made byesterifying the carboxyl group of the d,1 form of synthetic Vitamin Ewith PEG 1000. It forms a clear liquid when dissolved 20% in water. Thistocopheryl polyethylene glycol is a water-soluble preparation of afat-soluble vitamin (vitamin E), for example, as disclosed in U.S. Pat.Nos. 3,102,078 and 2,680,749 and U.S. Published Application Nos.2007/0184117 and 2007/0141203. The PEG moiety of alternative TPGSsurfactants can have a molecular weight range of about 200 or 200 to20,000 or about 20,000 Da. Also exemplary of the TPGS surfactant thatcan be used in the provided compositions is the Water Soluble NaturalVitamin E (TPGS), sold by ZMC-USA, The Woodlands, Texas. Any knownsource of TPGS can be used. Typically, the TPGS surfactant is GRAS andKosher certified. TPGS typically has an HLB value of between 16 or about16 and 18 or about 18.

As used herein, “particle size” and “average particle size” refersynonymously to the diameter of particles in the provided liquids, forexample, the droplet diameter or micelle diameter in an emulsion.Typically, the dilution compositions, made by diluting the providedpre-emulsion compositions, have a particle size of less than about 1000nm, typically, less than 500 nm or less than about 500 nm, typicallyless than 300 or about 300 nm, for example, less than 250 nm or about250 nm, for example, less than 200 nm or less than about 200 nm, forexample, less than or less than about 5, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80,90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 nm. In oneexample, the dilution compositions yielded by diluting the pre-emulsioncompositions have a particle size between 10 nm or about 10 nm and 1000nm or about 1000 nm, for example, between 15 nm or about 15 nm and 500nm or about 500 nm, for example, between 15 nm or about 15 nm and 300 nmor about 300 nm, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,150, 160, 170, 180, 190, 200 nm or more. Typically, the providedpre-emulsion compositions are formulated such that, dilution of thepre-emulsion composition in an aqueous medium yields a liquid dilutioncomposition having an appropriate particle size, for example, between 15nm or about 15 nm and 500 nm or about 500 nm. Information aboutparticles in the liquids alternatively be expressed in terms of particlenumber, for example, ppm (parts per million) or percent solids, in theliquids.

As used herein, visible particles are particles, for example, in aliquid, for example, an emulsion, that are visible when viewing theliquid with the naked eye (e.g. without magnification). In one example,the visible particles are particles that are observed by the artisanformulating the compositions, for example, the pre-emulsion compositionsor the aqueous liquid dilution compositions containing the dilutedpre-emulsion compositions. In one example, the provided compositionscontain no visible particles. In another example, the compositionscontain few visible particles, for example, no more visible particlesthan another liquid, for example, a beverage. The presence of visibleparticles and the number of visible particles is determined by empiricalobservation.

As used herein, visible crystals are crystals, for example, in a liquid,for example, an emulsion, that are visible when viewing the liquid withthe naked eye (e.g. without magnification). In one example, the visiblecrystals are crystals that are observed by the artisan formulating thecompositions, for example, the pre-emulsion compositions or the aqueousliquid dilution compositions containing the diluted pre-emulsioncompositions. In one example, the provided compositions contain novisible crystals. In another example, the compositions contain fewvisible crystals, for example, no more visible crystals than arecontained in another liquid, for example, a beverage. The presence ofvisible crystals is determined by empirical observation.

As used herein, “turbidity” is a measure of the cloudiness or hazinessof a liquid, caused by particles in suspension in the liquid. Turbiditycan measured optically, for example, using a nephelometer, an instrumentwith a light and a detector. The nephelometer measures turbidity bydetecting scattered light resulting from exposure of the liquid to anincident light. The amount of scattered light correlates to the amountof particulate matter in the liquid. For example, a beam of light willpass through a sample with low turbidity with little disturbance.

Turbidity can measured optically, for example, by using a nephelometer,an instrument with a light and a detector. The nephelometer measuresturbidity by detecting scattered light resulting from exposure of theliquid to an incident light. The amount of scattered light correlates tothe amount of particulate matter in the liquid. For example, a beam oflight will pass through a sample with low turbidity with littledisturbance. Other methods for measuring turbidity are well known andcan be used with the provided methods and compositions. The units of aturbidity value measured with a nephelometer are NephelomtetricTurbidity Units (NTU). In one example, the provided compositions, forexample, the aqueous liquid dilution compositions containing the dilutedpre-emulsion compositions have low turbidity, for example, a turbidityvalue (NTU) of 30 or about 30; or an NTU value of less than 30 or about30, for example, less than 29 or about 29, less than 28 or about 28,less than 27 or about 27, less than 26 or about 26, less than 25 orabout 25, less than 24 or about 24, less than 23 or about 23, less than22 or about 22, less than 21 or about 21, less than 20 or about 20, lessthan 19 or about 19, less than 18 or about 18, less than 17 or about 17,less than 16 or about 16, less than 15 or about 15, less than 14 orabout 14, less than 13 or about 13, less than 12 or about 12, less than11 or about 11, less than 10 or about 10, less than 9 or about 9, lessthan 8 or about 8, less than 7 or about 7, less than 6 or about 6, lessthan 5 or about 5, less than 4 or about 4, less than 3 or about 3, lessthan 2 or about 2, less than 1 or about 1; or 29 or about 29, 28 orabout 28, 27 or about 27, 26 or about 26, 25 or about 25, 24 or about24, 23 or about 23, 22 or about 22, 21 or about 21, 20 or about 20, 19or about 19, 18 or about 18, 17 or about 17, 16 or about 16, 15 or about15, 14 or about 14, 13 or about 13, 12 or about 12, 11 or about 11, 10or about 10, 9 or about 9, 8 or about 8, 7 or about 7, 6 or about 6, 5or about 5, 4 or about 4, 3 or about 3, 2 or about 2, 1 or about 1, or 0or about 0. In another example, the turbidity value of the aqueousliquid dilution composition is less than 1000 or less than about 1000,less than 500 or less than about 500, less than 300 or less than about300, less than 250 or less than about 250, 200 or less than about 200,for example, 200, 175, 150, 100, 50, 25 or less.

As used herein, a turbid liquid is one that is thick or opaque withvisible particles in suspension, for example, a liquid that is cloudy ormuddy in appearance.

As used herein, “clear” can be used to describe a composition asprovided herein, for example, the aqueous liquid dilution compositionscontaining the diluted pre-emulsion compositions. In one example, aclear liquid is one that does not appear cloudy by empirical observation(e.g. to the naked eye) and/or does not contain particles or crystalsthat are visible to the naked eye, or that does not exhibit “ringing.”In another example, a clear liquid is one that has a low or relativelylow turbidity value, for example an NTU value, that is less than orequal to a desired NTU value. In one example, a clear liquid has an NTUvalue of less than 300 or less than about 300, typically less than 250or less than about 250, typically less than 200 or less than about 200,for example, 200, 175, 150, 100, 50, 25 or less. In another example, aliquid is clear if it has a turbidity value (NTU) of 30 or about 30; oran NTU value of less than 30 or about 30, for example, less than 29 orabout 29, less than 28 or about 28, less than 27 or about 27, less than26 or about 26, less than 25 or about 25, less than 24 or about 24, lessthan 23 or about 23, less than 22 or about 22, less than 21 or about 21,less than 20 or about 20, less than 19 or about 19, less than 18 orabout 18, less than 17 or about 17, less than 16 or about 16, less than15 or about 15, less than 14 or about 14, less than 13 or about 13, lessthan 12 or about 12, less than 11 or about 11, less than 10 or about 10,less than 9 or about 9, less than 8 or about 8, less than 7 or about 7,less than 6 or about 6, less than 5 or about 5, less than 4 or about 4,less than 3 or about 3, less than 2 or about 2, less than 1 or about 1;or 29 or about 29, 28 or about 28, 27 or about 27, 26 or about 26, 25 orabout 25, 24 or about 24, 23 or about 23, 22 or about 22, 21 or about21, 20 or about 20, 19 or about 19, 18 or about 18, 17 or about 17, 16or about 16, 15 or about 15, 14 or about 14, 13 or about 13, 12 or about12, 11 or about 11, 10 or about 10, 9 or about 9, 8 or about 8, 7 orabout 7, 6 or about 6, 5 or about 5, 4 or about 4, 3 or about 3, 2 orabout 2, 1 or about 1, or 0 or about 0. In another example, a clearliquid is one that has a small or relatively small average particle size(e.g. less than 1000 nm or about 1000 nm, typically less than 500 nm orless than about 500 nm, typically less than 300 nm or about 300 nm,typically less than 250 nm or about 250 nm, typically less than 200 nmor about 200 nm, for example, less than 150 or about 150 nm, less than100 nm or about 100 nm, less than 75 nm or about 75 nm, less than 50 nmor about 50 nm, less than 25 nm or about 25 nm or less than 10 nm orabout 10 nm), for example, less than or less than about 5, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180,190, or 200 nm.

In another example, clarity is expressed relatively. For example, it canbe desired that a particular composition is equally as clear, about asclear, or more clear than another liquid (as measured empirically, or bymeasuring turbidity value or particle size). For example, clarity can beassessed relative to another aqueous liquid dilution composition, forexample, a beverage For example, In one example, a liquid is clear if itis similar in appearance to another clear liquid, for example, abeverage, for example, water. For example, it can be desired that acomposition has a particle size that is less than or equal to anotherliquid, for example, a beverage. In another example, it can be desiredthat a composition has a turbidity value that is less than or equal toanother liquid, for example, a beverage. In another example, it can bedesired that a composition appears more clear or as clear as anotherliquid, for example, a beverage, for example, by having no more visibleparticles, no more crystal formation and/or no more cloudiness than theother liquid. In one example, the provided compositions are clear. Inanother example, they are relatively clear or as clear as or about asclear as another liquid, for example, a beverage that does not containthe non-polar compound or pre-emulsion composition.

As used herein, “hydrophilic” refers to ingredients and/or compoundshaving greater solubility in aqueous liquids, for example, water, thanin fats, oils and/or organic solvents (e.g. methanol, ethanol, ethylether, acetone and benzene).

As used herein, “non-polar” “lipophilic” and “lipid-soluble”synonymously refer to compounds (e.g. non-polar compounds) and/oringredients, for example, non-polar active ingredients, which havegreater solubility in organic solvents (e.g. ethanol, methanol, ethylether, acetone, and benzene) and in fats and oils, than in aqueousliquids, for example, water. Non-polar compounds include drugs,hormones, vitamins, nutrients and other lipophilic compounds. Typically,the non-polar compounds used in the provided compositions are poorlywater soluble, for example, water insoluble or compounds having lowwater solubility. Exemplary non-polar compounds include non-polar activeingredients, for example, lipid-soluble drugs, hormones, essential fattyacids, for example, polyunsaturated fatty acids (PUFA), for example,omega-3 and omega-6 fatty acids, vitamins, nutrients, neutraceuticals,minerals and other compounds. Additional exemplary non-polar compoundsare described herein. The provided compositions can be formulated withany non-polar compound, for example, non-polar active ingredient.

As used herein, non-polar active ingredient refers to a non-polarcompound that, when administered to a subject, for example, a human,induces or is proposed to induce a desired biological response, such asaltering body function at the cellular, tissue, organ or other level,and/or altering cosmetic appearance or other property, or a non-polarcompound that is ingested in order to achieve a desired effect.Non-polar active ingredients can be any synthetic or natural non-polaringredient or compound, including a pharmaceutical, drug, therapeutic,nutritional supplement, herb, hormone or other ingredient. Non-polaractive ingredients can include the non-polar active ingredients listedherein, as well as other pharmaceutically acceptable or food-gradeactive derivatives of the active ingredients, for example, salts,esters, amides, prodrugs, active metabolites, isomers, fragments,analogs, and the like. Active ingredients can include compounds provento have a desired effect and also compounds thought to produce sucheffects, for example, compounds typically ingested for nutritionalsupplementation purposes.

As used herein, a subject includes an animal, typically a mammal,typically a human.

As used herein, additives include anything that one can add to a food,beverage, or other human consumable, to enhance one or more of itsnutritional, pharmaceutical, dietary, health, nutraceutical, healthbenefit, energy-providing, treating, holistic, or other properties. Forexample, provided herein are compositions and methods for preparingfoods, beverages and other aqueous human consumables, that include oneor more additives, typically oil based additives (e.g. non-polarcompounds), such as nutraceuticals, pharmaceuticals, vitamins, typicallyoil soluble vitamins, for example, Vitamin D, E and A, minerals, fattyacids, such as essential fatty acids, e.g. polyunsaturated fatty acids,for example, omega-3 fatty acids and omega-6 fatty acids, for example,ALA, DHA, EPA, GLA, CLA, saw palmetto extract, flaxseed oil, fish oil,algae oil, phytosterols, and Coenzymes, for example, Coenzyme Q10 andother additives.

As used herein, an effective amount of an additive, such as a non-polarcompound (e.g. non-polar active ingredient) refers to the quantityand/or concentration of the additive necessary for preventing, curing,ameliorating, arresting or partially arresting a symptom of a disease ordisorder, or the quantity and/or concentration desired by an individualfor intake, such as daily intake, and/or nutritional supplementation,for example, an amount sufficient to enhance the nutritional,pharmaceutical, nutraceutical, health or energy property of a food,beverage, or other consumable. In some examples, it is desired that theprovided compositions, for example, and/or the liquid dilutioncompositions, contain an effective amount of a particular non-polarcompound, for example, a particular amount per volume or weight of thecomposition.

In one example, an effective amount is a concentration or amount of apre-emulsion composition where at least 25 mg or about 25 mg, typicallyat least 35 mg, for example, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220,230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 425, 450,475, 500, 550, 600, 700, 800, 900, 1000, 1500, 2000 mg, or more, of thenon-polar active ingredient, is contained in at least 8 fluid ounces ofan aqueous medium, e.g. a beverage.

As used herein, unit dose form refers to physically discrete unitssuitable for human and animal subjects and packaged individually as isknown in the art.

As used herein, “water insoluble” refers to a property of a compound,none of which dissolves when the compound is mixed with water, forexample, when mixed with water at room temperature, for example, between25 and 50° C. or between about 25 and 50° C. In one example, thenon-polar compounds are water insoluble. In another example, thenon-polar compounds in the provided compositions are slightly soluble inwater, for example, having low water solubility.

As used herein, low water solubility refers water solubility of lessthan 30 or about 30 mg/mL, typically less than 20 mg/mL or about 20mg/mL, typically, less than 10 mg/mL or about 10 mg/mL, typically lessthan 1 mg/mL or about 1 mg/mL, for example, solubility in water of 30,29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12,11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 mg/mL or less, for example, when mixedwith water at room temperature, for example, between 25 and 50° C. orbetween about 25 and 50° C. As used herein, poorly water soluble can beused to refer to compounds, for example, non-polar compounds that arewater insoluble or have low water solubility.

As used herein, a non-aqueous composition is a composition containingcontain none or very little hydrophilic ingredient, for example,containing less than 5% or about 5%, by weight, hydrophilic ingredients,for example, less than 4% or about 4%, less than 3% or about 3%, lessthan 2% or about 2%, less than 1% or about 1%, or 0% or about 0%, byweight, hydrophilic ingredient(s).

As used herein, “waxy” is used to describe compositions and materials,typically oil-soluble compositions or materials, that are similar inconsistency to one or more waxes. Typically, the solid pre-emulsioncompositions provided herein have a waxy consistency at roomtemperature. Compositions and compounds having “waxy” consistenciestypically have melting points or melting ranges above ambienttemperature (e.g. above room temperature, for example, above 25° C. orabout 25° C.), meaning they are either solid or semi-solid (e.g. creamy)at room temperature. Typically, waxy compositions are of relatively lowviscosity a little above their liquefying point. Exemplary of waxes,which have waxy consistencies, are natural waxes, including waxes ofvegetal origin, such as purcelline, shea butter, cocoa butter, Japanwax, esparto gras wax, cork wax, Guaruma wax, rice shoot wax, Ouricurywax, montan wax, sunflower wax, ceresine wax, sugar cane wax, carnaubawax, candelilla wax, lanolin, fruit-derived waxes, such as orange wax,lemon wax, grapefruit wax and bayberry wax, and the like; waxes ofanimal origin, such as beeswax, woolwax, spermateci and bear fat,shellac wax, and the like; mineral waxes such as ceresine and ozokeritewaxes; and synthetic waxes, including petroleum-based waxes such asparaffin, petrolatum, micro wax, polyalkylene and polyethyleneglycolwaxes, e.g. polyethylene wax; waxes based on chlorinated naphthalenessuch as ‘Halowax’, synthetic hydrocarbon waxes, and the like.

As used herein, a non-aqueous composition (e.g. a non-aqueouspre-emulsion composition) is a composition that contains none, or verylittle of, any hydrophilic ingredient, for example, containing less than10% or about 10%, typically less than 5% or about 5%, by weight,hydrophilic ingredients, for example, less than 4% or about 4%, lessthan 3% or about 3%, less than 2% or about 2%, less than 1% or about 1%,or 0% or about 0%, by weight, hydrophilic ingredient(s).

As used herein, liquid composition is used to refer to any liquid, forexample, a composition that is a liquid at room temperature, forexample, at 25° C. or about 25° C., or at a temperature of between 25°C. or about 25° C. and 50° C. or about 50° C. Exemplary of the providedliquid compositions are aqueous liquid dilution compositions into whichone or more pre-emulsion composition has been diluted, for example,aqueous liquid dilution compositions containing the diluted pre-emulsioncompositions. In this example, the non-polar compound and otherlipophilic compounds form a dispersion phase within the aqueous liquidin an emulsion (e.g. nanoemulsion).

As used herein, “liquid dilution composition” “dilution composition” and“liquid dilution” are used synonymously to refer to a composition thatcontains one or more of the provided pre-emulsion compositions (e.g. thepre-emulsion compositions containing the non-polar compound(s)), dilutedin a liquid, for example, an aqueous medium. Exemplary of the providedliquid dilution compositions are aqueous liquid dilution compositions,for example, beverages or other liquids containing the pre-emulsioncompositions, for example, water, sauces, soups, syrups, soda, juice,for example, fruit juice, milk, coffee, tea, nutritional beverages,sports drinks, energy drinks, vitamin-fortified beverages, flavoredwater, and other beverages containing the diluted pre-emulsioncompositions.

As used herein, aqueous liquid dilution compositions are liquid dilutioncompositions that are primarily aqueous, for example, a compositioncomprising a pre-emulsion composition diluted in an aqueous medium, forexample, water or other beverage. It is not necessary that the aqueousliquid dilution composition is completely aqueous. For example, theaqueous liquid dilution compositions can contain an aqueous portion, forexample, an aqueous continuous phase, as well as an additional portion,for example, a dispersion phase, for example, a lipophilic dispersionphase. Typically, the lipophilic dispersion phase contains one or morelipophilic substances, for example, one or more non-polar compounds, forexample, non-polar active ingredients.

In one example, the dispersion phase of the aqueous liquid dilutioncomposition has a small droplet (particle) size, for example, a particlesize of less than 1000 or about 1000, typically less than 500 or about500, typically less than 300 or about 300 nm, typically less than 250 orabout 250 nm, typically less than 200 or about 200 nm, for example, aparticle size equal to, less than or less than about 5, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or200 nm. Exemplary of the provided aqueous liquid dilution compositionsare beverages, for example, water, soda, juice, for example, fruitjuice, milk, coffee, tea, nutritional beverages, sports drinks, energydrinks, vitamin-fortified beverages, flavored water, and otherbeverages. Typically, the aqueous liquid dilution compositions arebeverages including the non-polar compound, for example, beveragescontaining the diluted pre-emulsion compositions.

As used herein, “oil phase” can be used to refer to the portion of theliquid dilution composition containing one or more lipophilicingredients and/or amphiphilic ingredients, and is, in general, thelipid-soluble phase. Typically, the oil phase is the dispersion phase inthe provided emulsion compositions.

As used herein, “water phase” is used to refer to the portion of theliquid dilution composition that contains one or more hydrophilicingredients and/or amphiphilic ingredient. Typically, the water phase isthe continuous phase.

As used herein, an initial pre-emulsion composition is a pre-emulsioncomposition that is made in the provided methods for formulating thepre-emulsion compositions. Typically, the initial pre-emulsioncomposition is made by selecting ingredients, for example,surfactant(s), non-polar compound(s), and, optionally, other ingredients(e.g. preservative(s) and/or solvent(s)), and selecting startingconcentrations of the ingredients from an appropriate concentrationrange, as described herein. The initial pre-emulsion composition can beformulated based on parameters of an existing pre-emulsion composition,and/or according to the ingredients and concentration ranges providedherein. Using the provided formulation methods, the initial pre-emulsioncomposition is evaluated, for example, to determine whether thepre-emulsion composition has one or more desirable properties, forexample, clarity. In one example, changes are made to the formulation ofthe initial pre-emulsion composition, as described herein. In anotherexample, no changes are made and the formula of the initial pre-emulsioncomposition is used to make the pre-emulsion composition.

As used herein, stability refers to a desirable property of the providedcompositions, for example, the ability of the provided compositions toremain free from one or more changes over a period of time, for example,at least or over 1, 2, 3, 4, 5, 6 or more days, at least or over 1, 2,3, 4, or more weeks, at least or over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12 or more months, or at least or over 1, 2, 3, 4 or more years. In oneexample, the composition is stable if it is formulated such that itremains free from oxidation or substantial oxidation over time. Inanother example, the stable compositions remain clear over time. Inanother example, the stable compositions remain safe and/or desirablefor human consumption over time. In one example, stability refers to thelack of precipitates forming in the compositions over the period oftime. In a related example, stability refers to the lack of “ringing”over the period of time. In another example, the composition is stableif it does not exhibit any visible phase separation over a period oftime, for example, after 24 hours, after one week or after one month. Inone example, the compositions are stable if they exhibit one or more ofthese described characteristics, over time, when kept at a particulartemperature. In one example, the compositions remain stable at roomtemperature, for example, 25° C. or about 25° C. In another example, thecompositions remain stable at between 19° C. and 25° C. In anotherexample, the compositions remain stable at refrigerated temperatures,for example, 4° C. or about 4° C., or at frozen temperature, forexample, at −20° C. or about −20° C.

As used herein, stabilize means to increase or improve the stability ofa composition.

As used herein, room temperature and ambient temperature are used todescribe a temperature that is common in one or more enclosed spaces inwhich human beings typically are or reside. Room temperature can vary,but generally refers to temperatures between 19° C. or about 19° C. and25° C. or about 25° C. When a composition is stored at room temperature,it should be understood it is generally kept at a temperature withinthis range or about within this range.

As used herein, refrigerated temperature refers to a temperature that iscommon in a refrigerator, for example, a household or restaurantrefrigerator, for example, a temperature that is cooler than roomtemperature, but typically a few degrees above the freezing point ofwater (0° F. or about 0° F., or −19° C. or −20° C.). Typically,refrigerated temperatures are between about 10° C. or about 10° C. and0° C. or about 0° C., for example, 4° C. or about 4° C. When acomposition is stored at a refrigerated temperature, it should beunderstood that it is kept at a temperature common to household orindustrial refrigerators.

As used herein, frozen temperature refers to a temperature around orbelow the freezing point of water, e.g. a temperature commonly used in ahousehold freezer, for example, 0° F. or about 0° F., for example, −19°C. or about −19° C. or −20° C. or about −20° C., or colder.

As used herein, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to compound, comprising “an extracellular domain” ”includes compounds with one or a plurality of extracellular domains.

As used herein, ranges and amounts can be expressed as “about” aparticular value or range. About also includes the exact amount. Hence“about 5 grams” means “about 5 grams” and also “5 grams.' It also isunderstood that ranges expressed herein include whole numbers within theranges and fractions thereof. For example, a range of between 5 gramsand 20 grams includes whole number values such as 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 and 20 grams, and fractions within therange, for example, 5.25, 6.72, 8.5, 11.95, etc grams.

As used herein, “optional” or “optionally” means that the subsequentlydescribed event or circumstance does or does not occur and that thedescription includes instances where said event or circumstance occursand instances where it does not. For example, an optionally variantportion means that the portion is variant or non-variant. In anotherexample, an optional ligation step means that the process includes aligation step or it does not include a ligation step.

As used herein, “ringing” refers to the formation of a whitish or opaquering around a container containing a liquid, for example, an aqueousliquid, for example a beverage, for example, a liquid dilutioncomposition containing an emulsion or nanoemulsion. Typically, the ringforms around the perimeter of the container, typically at the surfacelevel of the liquid in the container, for example, at the neck of thecontainer. Ringing can occur over time and, if it occurs over a shortperiod of time, can be a sign of instability. Ringing typically isundesirable, particularly in the case of a liquid for human consumption,for example, a beverage. Typically, the provided stable compositions donot exhibit “ringing” or are stable, without ringing, for a long periodof time, for example, days, weeks, months or years. In one example, thecompositions are free from ringing over time, when kept, for example, atroom temperature, refrigerated and/or frozen. These desired propertiesof the provided compositions related to ringing can be affected by theparticle size of the compositions, which can be influenced by selectionof particular ingredients and concentrations of ingredients, forexample, by properties of the surfactant(s), for example, the HLB of thesurfactant(s).

As used herein, fatty acid refers to straight-chain hydrocarbonmolecules with a carboxyl (COOH) group at one end of the chain.

As used herein, polyunsaturated fatty acid and PUFA are usedsynonymously to refer to fatty acids that contain more than onecarbon-carbon double bond in the carbon chain of the fatty acid. PUFAs,particularly essential fatty acids, are useful as dietary supplements.

As used herein, essential fatty acids are PUFAs that mammals, includinghumans, cannot synthesize using any known chemical pathway. Thus,essential fatty acids must be obtained from diet or by supplementation.Exemplary of essential PUFA fatty acids are omega-3 ({acute over (ω)}3;n-3) fatty acids and the omega-6 ({acute over (ω)}-6; n-6) fatty acids.

As used herein, omega-3 ({acute over (ω)}3; n-3) fatty acids aremethylene interrupted polyenes, which have two or more cis double bonds,separated by a single methylene group and in which the first double bondappears at the third carbon from the last ({acute over (ω)}) carbon.Omega-3 fatty acids are used as dietary supplements, for example, fordisease treatment and prevention. In one example, the providedcompositions contain non-polar active ingredients that contain at leastone omega-3 fatty acids. Exemplary of Omega-3 fatty acids areAlpha-Linolenic acid (a-Linolenic acid; ALA) (18:3{acute over (ω)}3) (ashort-chain fatty acid); Stearidonic acid (18:4{acute over (ω)}3) (ashort-chain fatty acid); Eicosapentaenoic acid (EPA) (20:5{acute over(ω)}3); Docosahexaenoic acid (DHA) (22:6{acute over (ω)}3);Eicosatetraenoic acid (24:4{acute over (ω)}3); Docosapentaenoic acid(DPA, Clupanodonic acid) (22:5{acute over (ω)}3); 16:3{acute over (ω)}3;24:5{acute over (ω)}3 and nisinic acid (24:6{acute over (ω)}3). Longerchain Omega-3 fatty acids can be synthesized from ALA (the short-chainomega-3 fatty acid). Exemplary of non-polar active ingredientscontaining omega-3 fatty acids are non-polar active ingredientscontaining DHA and/or EPA, for example, containing fish oil, krill oiland/or algae oil, for example, microalgae oil, non-polar activeingredients containing ALA, for example, containing flaxseed oil.

As used herein, omega-6 ({acute over (ω)}-6; n-6) fatty acids aremethylene interrupted polyenes, which have two or more cis double bonds,separated by a single methylene group and in which the first double bondappears at the sixth carbon from the last ({acute over (ω)}) carbon. Inone example, the provided compositions contain non-polar activeingredients that contain at least one omega-3 fatty acids. Exemplary ofOmega-6 fatty acids are Linoleic acid (18:2{acute over (ω)}6) (ashort-chain fatty acid); Gamma-linolenic acid (GLA) (18:3{acute over(ω)}6); Dihomo gamma linolenic acid (DGLA) (20:3{acute over (ω)}6);Eicosadienoic acid (20:2{acute over (ω)}6); Arachidonic acid (AA)(20:4{acute over (ω)}6); Docosadienoic acid (22:2{acute over (ω)}6);Adrenic acid (22:4{acute over (ω)}6); and Docosapentaenoic acid(22:5{acute over (ω)}6). Exemplary of non-polar active ingredientscontaining omega-6 fatty acids are ingredients containing GLA, forexample, borage oil. Also exemplary of PUFA-containing non-polar activeingredients are compounds containing conjugated fatty acids, forexample, Conjugated linoleic acid (CLA) and compounds containing sawpalmetto extract.

As used herein, algae oil refers to any oil derived from marinedinoflagellates in, for example, microalgae, for example,Crypthecodinium sp, particularly, Crypthecodinium cohnii. In oneexample, algae oil is used as a non-polar compound, for example, as anactive ingredient, in the provided compositions. The algae oil typicallycontains DHA. In one example, the algae oil is also a source of EPA.

As used herein, fish oil refers to any oil derived from any fish,typically a cold water fish, for example, from fish tissue, for example,from frozen fish tissue, for example, from cod liver. In one example,fish oil is used as a non-polar compound, for example, an activeingredient, in the provided compositions. The fish oil typicallycontains DHA. In one example, the fish oil also contains EPA.

As used herein, preservative and preservativer are used synonymously torefer to ingredients that can improve stability of the providedcompositions. Preservatives, particularly food and beveragepreservatives, are well known. Any known preservative can be used in theprovided compositions. Exemplary of the preservatives that can be usedin the provided compositions are oil soluble preservatives, for example,benzyl alcohol, Benzyl Benzoate, Methyl Paraben, Propyl Paraben,antioxidants, for example, Vitamin E, Vitamin A Palmitate and BetaCarotene. Typically, a preservative is selected that is safe for humanconsumption, for example, in foods and beverages, for example, a GRAScertified and/or Kosher-certified preservative, for example, benzylalcohol.

As used herein, solvent refers to an ingredient, for example, an oil,that is used to dissolve a compound, typically, the non-polar compound,for example, the non-polar active ingredient. For example, the solventcan be used to dissolve the non-polar active ingredient prior to orsimultaneous with its incorporation into the composition. Typically, thesolvent is an oil that is included in the composition in addition to thenon-polar compound. For example, the solvent typically is not thenon-polar compound. Certain compounds, for example, flaxseed oil andsafflower oil, can be both solvents and non-polar active ingredients.Typically, the solvent contains one or more oils, typically oils otherthan the non-polar active ingredient or oil(s) not contained in theactive ingredient. When a solvent is included in the pre-emulsioncomposition, it typically is used to dissolve the non-polar compoundbefore mixing with the other ingredients, for example, before mixingwith the other ingredients. In one example, use of a solvent reduces thecrystal size and/or increase the clarity of the aqueous liquid dilutioncomposition containing the diluted pre-emulsion composition. Exemplaryof solvents that can be used in the provided pre-emulsion compositionsare oils (in addition to the non-polar active ingredient), for example,Vitamin E oil, flaxseed oil, CLA, Borage Oil, D-limonene, Canola oil,corn oil, MCT oil and oat oil. Other oils also can be used. Exemplary ofthe Vitamin E oil, used as a solvent in the provided compositions, isthe oil sold by ADM Natural Health and Nutrition, Decatur, Ill., underthe name Novatol™ 5-67 Vitamin E (D-alpha-Tocopherol; ADM product code410217). This Vitamin E oil contains at least 67.2% Tocopherol andapproximately 32.8% soybean oil. In one example, the solvent is referredto, synonymously as “solubilizer.”

As used herein, “w/w,” “weight per weight,” “by weight” “% by weight”and “weight percent” are used synonymously used to express the ratio ofthe mass of one component of a composition compared to the mass of theentire composition. For example, when a particular ingredient represents1%, by weight (w/w) of a pre-emulsion composition, the mass of thatingredient is 1% of the mass of the entire pre-emulsion composition.Similarly, when the concentration of an ingredient is 50% (w/w) of thepre-emulsion composition, the mass of that ingredient is 50% of theentire mass of the pre-emulsion composition. Similarly, when acomposition and/or a compound contains 10%, by weight of an ingredient,the mass of the ingredient is 10% of the total mass of the compositionor compound. When only a concentration, or percentage (without units) islisted, it is to be understood that the concentration or percentage is aconcentration or percentage, by weight.

Similarly, as used herein “v/v,” “volume per volume,” “percent byvolume” and “volume percent” are used synonymously to express the ratioof the volume of one component of a composition and the volume of theentire composition.

As used herein, emulsion stabilizer refers to compounds that can be usedto stabilize and/or emulsify and/or change the viscosity of the providedcompositions, for example, the pre-emulsion composition and/or theaqueous compositions containing the diluted pre-emulsion compositions.In one example, the emulsion stabilizer increases the viscosity of theliquid pre-emulsion composition. In one example, one or more emulsionstabilizers is added, during formulation, after evaluation of an initialpre-emulsion composition, particularly if the oil and water phases ofthe aqueous liquid dilution composition resulting from dilution of theinitial pre-emulsion composition appear to be separating. Addition ofthe emulsion stabilizer can prevent separation of the oil and waterphases.

Exemplary of an emulsion stabilizer that can be used in the providedcompositions is a composition containing a blend of gums, for example,gums used as emulsifying agents, for example, a blend containing one ormore of xanthan gum, guar gum and sodium alginate, for example, theemulsion stabilizer sold under the brand name SALADIZER®, available fromTIC Gums, Inc. (Belcamp, Md.). Other gums can be included in theemulsion stabilizer, for example, gum acacia and sugar beet pectin.Other blends of similar gums can also be used as emulsion stabilizers.

As used herein, a pH adjuster is any compound, typically an acid or abase, that is capable of changing the pH of the provided compositions,for example, to reduce the pH of the composition or to increase the pHof the composition, typically without altering other properties of thecomposition, or without substantially altering other properties. pHadjusters are well known. Exemplary of the pH adjusters are acids, forexample, citric acid and phosphoric acid, and bases.

As used herein, flavor is any ingredient that changes, typicallyimproves, the taste and/or smell of the provided composition, forexample, the aqueous liquid dilution compositions, for example, thebeverages.

As used herein, “not more than” and “NMT” refer to a quantity that isless than or equal to the listed quantity. Similarly, “not less than”and “NLT” refer to a quantity that is greater than or equal to thelisted quantity.

As used herein, natural is used to refer to a composition, and/oringredients in the composition, that can be found in nature and is notsolely man-made. For example, benzyl alcohol is a natural preservative.Similarly, tocopheryl polyethylene glycol is a natural surfactant. Inone example, the natural composition/ingredient is GRAS and/orKosher—certified. Typically, the provided compositions are natural,semi-natural and/or contain one or more natural ingredients.

As used herein, “G.R.A.S.” and “GRAS” are used synonymously to refer tocompounds, compositions and ingredients that are “Generally Regarded asSafe” by the USDA, FDA for use as additives, for example, in foods,beverages and/or other substance for human consumption, for example, anysubstance that meets the criteria of sections 201 (s) and 409 of theU.S. Federal Food, Drug and Cosmetic Act. Typically, the compositionsprovided herein are GRAS certified.

As used herein, kosher is used to refer to substances that conform toJewish Kosher dietary laws, for example, substances that do not containingredients derived from non-kosher animals or ingredients that were notmade following kosher procedures. Typically, the compositions providedherein are Kosher certified.

As used herein, vessel refers to any container, for example, tanks,pots, vials, flasks, cylinders, and beakers, that can be used to containthe ingredients and/or phases of the provided compositions, during themethods for making the compositions. In one example (e.g. for theprovided scaled-up methods), the vessel is a tank, which is used to mixand/or heat one or more ingredients and/or phases of the compositions,for example, the pre-emulsion compositions. In one example, the tank isa mixing tank, which is used to mix (and optionally heat) one or moreingredients of the compositions. In one example, the tank is a packagingor holding tank, which holds the provided compositions after forming thecompositions, for example, the pre-emulsion compositions. A number oftanks are available for mixing ingredients. Typically, the tanks arecleaned, for example, rinsed, soaped and/or sanitized according to knowprocedures, prior to use and between uses. Typically, the tanks areequipped with one or more mixers, for example, a standard mixer and/orhomogenizer, which are used to mix the ingredients added to the tank. Inone example, the tank further is equipped with a heating and/or coolingdevice. For example, the tank can be a water-jacketed tank. Thetemperature of the water-jacketed tank is controlled through thewater-jacket, for example, to heat the contents, for example, whilemixing.

As used herein, transfer means refers to any equipment, combination ofequipment and/or system that can be used to transfer liquid, forexample, from one tank to another tank (e.g. from the mixing tank to thepackaging/holding tank), in the provided methods for making thecompositions. Exemplary of the transfer means are a transfer pump andappropriate fittings, for example, sanitary fittings, ball valves andtransfer hoses, for example, food grade hoses.

As used herein a mixer is any piece of equipment or combination ofequipment that can be used to mix ingredients in the provided methodsfor making the compositions, for example, standard mixers andhomoginizers (shears). For example, mixers can be used to mix theingredients of the compositions.

As used herein, standard mixers are mixers that are used to combine agroup of ingredients, or to mix one or more ingredients with a liquid,for example, with an emulsion, for example, to mix additionalingredients with the emulsion. Standard mixers can be any mixers thatmove the material, for example, the ingredients, during heating, forexample, to promote dissolving of the ingredients.

As used herein, “homogenizer” and “shear” are used to refer to mixerswith high shear, that typically are used after mixing the ingredients,for example, the ingredients of the pre-emulsion compositions. Thehomogenizers typically are capable of high-shear mixing, which canemulsify imiscible phases, e.g. phases of an emulsion, e.g. water/oilphases.

As used herein, a cooling apparatus is any piece of equipment orcombination of equipment that can be used with the provided methods tocool the compositions and phases and ingredients thereof, for example,during mixing and/or homogenizing.

Exemplary of the cooling apparatuses are coolers (chillers), forexample, recirculating coolers which can be attached, for example, to atank, for example, remotely or by a tank mounted in the cooler, torecirculate fluid from the tank, through the chiller and back to thetank, in order to rapidly cool and maintain the temperature of a mixtureduring mixing. Typically, the cooling apparatus can be used to cool aliquid to between 25° C. or about 25° C. and 45° C. or about 45° C., forexample, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44 or 45° C., typically between 25° C. and 43° C., typicallybetween 35° C. and 43° C., for example, 26.5° C.

As used herein, rapid cooling refers to a process by which acomposition, for example, a liquid composition, for example, a formingemulsion, is cooled to a desired temperature, for example, between 25°C. or about 25° C. and 45° C. or about 45° C., typically between 35° C.and 43° C., for example, 26.5° C., in less than 2 hours or about 2hours, typically less than 1 hour or about 1 hour, for example, in atleast between 30 minutes or about 30 minutes and 60 minutes or about 60minutes, for example, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59or 60 minutes.

As used herein, low heat refers to a temperature between 45° C. or about45° C. and 85° C. or about 85° C., for example, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85°C., for example, not more than 85° C. or about 85° C., typically notmore than 60° C. or about 60° C., typically, 60° C. or about 60° C. Inthe provided methods for making the pre-emulsion compositions, theingredients typically are heated, using low heat, in order to preservethe ingredients, for example, in order to prevent oxidation of theingredients, for example, the non-polar active ingredients, for example,the omega-3 containing compounds, for example, the DHA.

As used herein, “consisting essentially of,” means containing thefollowing list of ingredient(s), and not including any additional activeingredient, for example, not including any additional active drug orpharmaceutical. For example, a composition, for example, a pre-emulsioncomposition, consisting essentially of a listed plurality of ingredientscontains those particular ingredients and does not contain anyadditional active drug or pharmaceutical.

B. Compositions Containing Non-Polar Compounds

Provided herein are compositions containing non-polar compounds andmethods for making the compositions. Non-polar compounds are poorlywater soluble (e.g. having low water solubility or beingwater-insoluble). Generally, because of this poor water solubility, itcan be difficult to formulate non-polar compounds into compositions forhuman consumption, particularly aqueous compositions, for example, foodsand beverages. Poor water solubility also can contribute to poorbioavailability of non-polar compounds. Improved methods andcompositions for formulating non-polar compounds are needed.

Emulsions (e.g. oil-in-water emulsions) have been used to dispersenon-polar compounds in aqueous liquids. In general, emulsions arecolloidal dispersions of two immiscible liquids (e.g. oil and water orother aqueous liquid), containing a continuous and a dispersed phase. Inan oil-in-water emulsion, the dispersed phase is an oil phase and thecontinuous phase is an aqueous (water) phase. There remains a need,however, for improved emulsions (e.g. oil-in-water emulsions) containingnon-polar compounds in aqueous liquids, and methods and compositions forgenerating the improved emulsions. In particular, emulsions are neededthat are more suitable and desirable for human consumption of thenon-polar compounds, for example, in foods and beverages. For example,emulsions having improved clarity (e.g. small particle size, lowturbidity), stability (e.g. lack of separation), taste and smell, areneeded.

Among the provided compositions are improved emulsions (e.g. liquiddilution compositions). Emulsions are provided that contain thenon-polar compounds dispersed in aqueous liquid and have desirableproperties, including improved clarity, stability, smell and taste. Alsoprovided are compositions that can be diluted to generate the emulsions(e.g. pre-emulsion compositions). The provided compositions and methodsfor making the compositions can be used to formulate any non-polarcompound in aqueous compositions.

Typically, the provided emulsions containing the non-polar compounds(e.g. the liquid dilution compositions) are nanoemulsions, which areemulsions having dispersed droplets (particles) with diameters less than1000 nm or less than about 1000 nm, typically, less than 500 nm or lessthan about 500 nm, typically less than 300 or about 300 nm, typicallyless than 250 or less than about 250 nm, typically less than 200 nm orless than about 200 nm, for example, less than or less than about 5, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170,180, 190, or 200 nm. Typically, the provided nanoemulsion compositionsare oil-in-water nanoemulsions, containing the non-polar compoundsdispersed in aqueous liquid. The provided emulsion compositions arestabilized by one or more surfactants and/or co-surfactants and/oremulsion stabilizers. Surfactants form an interfacial film in theemulsion, between the oil and water phase, providing stability.Typically, the nanoemulsions of the provided compositions containmicelles, in which one or more surfactant surrounds the non-polar activecompound. The micelles are dispersed in the water phase. Exemplary ofthe nanoemulsions are liquid dilution compositions, including aqueousdilution compositions, for example, clear aqueous compositionscontaining the non-polar compounds. Typically, the liquid dilutioncompositions are made by diluting one or more of the providedpre-emulsion composition compositions.

Also among the provided compositions are pre-emulsion compositionscontaining the non-polar compounds, which can be diluted to make thenanoemulsions, e.g. the liquid dilution compositions. The pre-emulsioncompositions can be diluted, according to the provided methods, to formdilution compositions, for example, aqueous liquid dilutioncompositions. Typically, the pre-emulsion compositions are solidpre-emulsion compositions, which are not liquid (or gas) at roomtemperature (e.g. 25° C. or about 25° C.). Typically the solidpre-emulsion compositions have a waxy consistency at room temperature,and become liquid when heated, for example, when heated to 120° F., orabout 120° F. 125° F., or about 125° F., or 145° F., or about 145° F.,50° C. or about 50° C., 60° C. or about 60° C. Typically, the solidpre-emulsion compositions are non-aqueous, containing none or verylittle hydrophilic ingredient, for example, containing less than 5% orabout 5%, by weight, hydrophilic ingredients, for example, less than 4%or about 4%, less than 3% or about 3%, less than 2% or about 2%, lessthan 1% or about 1%, or 0% or about 0%, by weight, hydrophilicingredient(s).

The pre-emulsion compositions can be diluted, according to the providedmethods, into a medium, for example, an aqueous medium for example, abeverage, to form a liquid dilution composition (e.g. aqueous liquiddilution composition) containing the non-polar compound.

The compositions can be made using any non-polar compound. Exemplary ofnon-polar compounds that can be used in the provided compositions arenon-polar active ingredients, for example, pharmaceuticals,nutraceuticals, vitamins and minerals. Exemplary of non-polar activeingredients are Polyunsaturated Fatty Acids (PUFA)-containing compounds,for example, omega-3-containing active ingredients, for example,compounds containing ALA, DHA and/or EPA, for example, oils derived fromfish and microalgae, krill and/or flaxseed extract, andomega-6-containing non-polar active ingredients, for example,gamma-linolenic acid (GLA)-containing compounds, for example, borageoil; saw palmetto oil-containing compounds; conjugated fatty acidcontaining-ingredients, for example, Conjugated Linoleic acid(CLA)-containing compounds; coenzyme Q-containing active ingredients,for example, Coenzyme Q10 (CoQ10), typically oxidized CoQ10(ubidicarenone)-containing compounds; and compounds containingphytosterols (plant sterols). Additional exemplary non-polar activeingredients are described herein. Any non-polar compound can be used inthe provided compositions.

1. Pre-emulsion Compositions Containing the Non-polar Compounds

Exemplary of the provided compositions are pre-emulsion compositionscontaining one or more non-polar compounds. Typically, the pre-emulsioncompositions are solid compositions, which typically have a waxyconsistency, for example, the consistency of a substance such as wax,for example, a lip balm, at room temperature, for example, at 25° C. orabout 25° C., and become liquid at higher temperatures, for example whenheated to higher temperatures, for example, to 125° F. or about 125° F.,or to 50° C. or about 50° C. or to 60° C. or about 60° C.

The pre-emulsion compositions can be diluted into aqueous media, usingthe provided methods, to form the provided liquid dilution compositionscontaining the non-polar compounds. The pre-emulsion compositions areformulated such that dilution of the compositions, for example, inaqueous media, yields a composition having one or more desirableproperties, for example, clarity; safety; taste; smell; stability, forexample, lack of phase separation, “ringing” and/or precipitation overtime; and/or bioavailability. In one example, the desirable property isthe ability of the provided pre-emulsion composition to yield a clear orpartially clear aqueous liquid dilution composition when it is dilutedinto aqueous medium, for example, a beverage such as water. In anotherexample, the desirable property relates to the safety of thepre-emulsion compositions and/or the desirability of the pre-emulsioncompositions for human consumption, for example, in foods and beverages.In another example, it can be desirable that the pre-emulsioncomposition contains less than or equal to a particular concentration ofone or more ingredients. In another example, it can be desirable thatthe pre-emulsion composition contains greater than or equal to aparticular concentration of one or more ingredients.

In addition to the non-polar compounds, the pre-emulsion compositionscontain at least one surfactant. Typically, the surfactant has an HLBvalue between 14 or about 14 and 20 or about 20, for example, 14, 15,16, 17, 18, 19, 20, about 14, about 15, about 16, about 17, about 18,about 19 or about 20. Exemplary of suitable surfactants are tocopherolpolyethylene glycol succinate (TPGS) and other surfactants havingsimilar properties to TPGS, for example, other surfactants having HLBvalues between 14 or about 14 and 20 or about 20. Typically, thesurfactant is a natural surfactant, for example, a surfactant that isGRAS (generally recognized as safe) by the FDA and/or Kosher certified,for example, TPGS.

Typically, the pre-emulsion compositions further contain one or moreadditional ingredients. Exemplary of additional ingredients that can beincluded in the pre-emulsion compositions are preservatives, solvents,co-surfactants, emulsion-stabilizers and flavoring agents, as describedherein.

Typically, the pre-emulsion compositions are formulated such that, whendiluted into an aqueous medium (e.g. water), they yield a dilutioncomposition that is a nanoemulsion, in which the non-polar compound(s)are present in micelles. These micelles, containing the non-polarcompound surrounded by the one or more surfactants, facilitate thedispersion of the non-polar compound among the polar solvent(s) of theaqueous medium in the dilution compositions. Typically, the pre-emulsioncompositions are formulated such that the micelles in the dilutioncomposition have a small or relatively small particle size, for example,less than 1000 or about 1000 nm, less than 500 or about 500 nm,typically less than 300 or about 300 nm, typically less than 250 orabout 250 nm, typically less than 200 or about 200 nm, for example, 0,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 95, 100, 125, 150 or 200 nm. Smaller particle sizecorrelates with increased clarity of the dilution compositions thatresult from diluting the pre-emulsion compositions. For example, aliquid with a smaller particle size is more clear than a liquid with alarger particle size. Small particle size also can contribute to otherdesirable properties, for example, stability.

A number of parameters of the pre-emulsion compositions, includingingredients, their relative concentrations, and methods for making thepre-emulsion compositions, affect the particle size of the dilutioncompositions made by diluting the pre-emulsion compositions. Byextension, these parameters of the pre-emulsion compositions also affectthe desirable properties of the dilution compositions, for example, theclarity of the dilution compositions. In particular, the nature of thesurfactant, particularly the HLB of the surfactant, and the relativeconcentrations of the surfactant and the non-polar compound in thepre-emulsion composition, contribute to small particle size and clarityof the dilution compositions. Typically, several of these parameters andproperties relate to one another. For example, several of the parameterscontribute to the particle size, typically small particle size. Particlesize contributes directly to clarity of the aqueous liquid dilutioncompositions containing the pre-emulsion compositions. Particle sizealso can relate to other properties, for example, stability, lack of“ringing” and/or precipitate formation of the aqueous liquid dilutioncompositions containing the pre-emulsion compositions.

Accordingly, properties of the ingredients and their relativeconcentrations in the pre-emulsion compositions are important for theability of the pre-emulsion composition to yield desirable dilutioncompositions. Determining the appropriate ingredients, and relativeconcentrations thereof, that will yield dilution compositions havingdesirable properties, is carried out using provided methods forformulating the pre-emulsion compositions.

a. Formulating the Pre-emulsion Compositions

Using the provided formulation methods, the pre-emulsion compositionsare formulated by selecting ingredients and concentration ratios of theingredients that yield compositions having one or more desiredproperties. When formulating the pre-emulsion compositions, selectedingredients and starting concentrations are used to make initialpre-emulsion compositions, which typically are diluted, evaluated andmodified, if necessary.

As a first step in formulating the provided pre-emulsion compositions,one or more initial pre-emulsion compositions are made and evaluated fordesired properties. For this step, ingredients are selected, forexample, from one or more of the lists of ingredients provided below. Astarting concentration (weight percentage) of each selected ingredientis selected from within an appropriate concentration range for thatingredient or category of ingredient. For example, a starting surfactantconcentration is selected from within an appropriate surfactantconcentration range. In some cases, the initial pre-emulsion compositionis formulated based on the ingredients, and concentrations thereof, ofan existing pre-emulsion composition, having one or more desiredproperties.

The initial pre-emulsion composition(s) then is made, using the methodsfor making the pre-emulsion compositions, provided below, adding eachingredient at its starting concentration at the appropriate step. In oneexample, more than one initial pre-emulsion composition is made. Forexample, multiple initial pre-emulsion compositions, each having adifferent concentration of one or more ingredients, can be made andcompared. For example, multiple initial pre-emulsion compositions can bemade in order to test various representative concentrations within anappropriate concentration range for one or more particular ingredient.

In a typical example, the initial pre-emulsion composition is made byincluding at least one surfactant, having an HLB value between 14 orabout 14 and 20 or about 20, typically a tocopherol polyethylene glycolsuccinate (TPGS) surfactant.

In one example, the starting concentration of the surfactant is greaterthan 50% or about 50%, typically greater than 60% or about 60%,typically greater than 65% or about 65%, for example, greater than 70%or about 70%, for example, a starting concentration within theconcentration range of between 50% or about 50% and 95% or about 95%,between 60% or about 60% and 95% or about 95%, typically between 65% orabout 65% and 90% or about 90%, for example, between 69% or about 69%and 90% or about 90%, for example, between 69% or about 69% and 89% orabout 89%, for example, 65, 66, 67, 68, 69, 69.5, 69.9, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 79.5, 79.9, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 89.5, 89.9, or 90%, by weight, of the composition.

In another example, the starting concentration of the surfactant isgreater than 20% or about 20%, typically greater than 30% or about 30%,for example, between 30% or about 30% and 55% or about 55%, for example,between 30% or about 30% and 50% or about 50%, for example, between 30%or about 30% and 45% or about 45%, for example, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55%, by weight, of the composition. This example is typically usedfor pre-emulsion compositions where the non-polar active ingredientincludes a phytosterol.

Also in this typical example, the initial pre-emulsion compositionfurther includes at least one non-polar compound (e.g. non-polar activeingredient). In one example, the starting concentration of the non-polarcompound (e.g. active ingredient), or the total of all the one or morenon-polar compounds, is chosen from within a concentration range ofbetween 5% or about 5% and 35% or about 35%, typically between 10% orabout 10% and 30% or about 30%, for example, between 10% or about 10%and 20% or about 20%, or between 20% or about 20% and 30% or about 30%,for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, or 30%, by weight, of thecomposition.

In another example, the starting concentration of the non-polar compound(e.g. active ingredient), or the total of all the one or more non-polarcompounds, is chosen from within a concentration range of between 1% orabout 1% and 50% or about 50%. In this example, which typically is usedwhen using more than one non-polar active ingredient, the totalconcentration of the non-polar compounds is chosen from within aconcentration range of between 30% or about 30% and 55% or about 55%,for example between 40% or about 40% and 50% or about 50%, by weight, ofthe composition. Exemplary of starting concentrations for individualnon-polar active ingredients used in this example are between 1% and50%, for example, 1%, 10.5%, 34%, 45%, by weight of the composition, andother concentrations within the range.

In one example, the initial pre-emulsion composition further includesother ingredients, for example, preservative(s), for example, benzylalcohol; co-surfactant(s), for example, a phospholipid, for example,phosphatidylcholine; a solvent, for example, an oil, and/or an emulsionstabilizer. Typically, water is not added as an ingredient to thepre-emulsion composition.

After making the initial pre-emulsion composition(s), the pre-emulsioncomposition(s) is evaluated for one or more desired properties, forexample, the ability to form dilution compositions (e.g. clear dilutioncompositions or dilution compositions having a particular turbidityvalue, particle size or other property). The ability to form dilutioncompositions having one or more properties is assessed by diluting thepre-emulsion composition in aqueous medium, for example, diluting thepre-emulsion composition in the aqueous medium at a dilution factor ofbetween 1:10 or about 1:10 and 1:1000 or about 1:1000 or more, typicallybetween 1:10 or about 1:10 and 1:500 or about 1:500 or more, forexample, diluted not more than 1:10 or about 1:10, 1:20 or about 1:20,1:25 or about 1:25, 1:50 or about 1:50, 1:100 or about 1:100, 1:200 orabout 1:200, 1:250 or about 1:250, 1:300 or about 1:300, 1:400 or about1:400, 1:500 or about 1:500, for example, 1:10, 1:20, 1:25, 1:30, 1:35,1:40, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 1:100, 1:110,1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210,1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300,1:350, 1:400, 1:450, 1:500 or more. In one example, the dilution iscarried out by including one or more drops of the heated pre-emulsioncomposition in the aqueous medium, for example, in 25 mL or more of theaqueous medium.

After evaluation, the ingredients, and/or concentrations thereof, can beadjusted in order to generate the desired properties in the finalpre-emulsion composition. Typically, the concentration of the non-polarcompound and/or the surfactant is the concentration that is adjustedafter evaluating the initial pre-emulsion composition. Similarly, whenformulating multiple initial pre-emulsion compositions, one or more ofthe non-polar compound and the surfactant is/are varied among themultiple initial pre-emulsion compositions. In some cases, followingevaluation, it can be determined that additional ingredients (notincluded in the initial formulation) are needed or desirable forachieving the desired properties of a particular pre-emulsioncomposition. This process can be repeated until a pre-emulsioncomposition having the desired property or properties is generated.

i. Common Ingredients and Typical Concentration Ranges

Each of the provided pre-emulsion compositions contains at least onecompound, typically a non-polar compound (e.g. a non-polar activeingredient). Any non-polar compound can be formulated with the providedmethods and pre-emulsion compositions. Several exemplary non-polarcompounds that can be incorporated into the provided compositions aredescribed herein below. Typically, the non-polar compound is a non-polaractive ingredient, for example, an oil-based active ingredient, forexample, a polyunsaturated fatty acid (PUFA), a coenzyme Q or aphytochemical.

In one example, for formulating the initial pre-emulsion composition,the starting concentration of the non-polar compound, or the total ofall the one or more non-polar compounds, typically is chosen from withina concentration range of between 5% or about 5% and 35% or about 35%,typically between 10% or about 10% and 30% or about 30%, for example,between 10% or about 10% and 20% or about 20%, or between 20% or about20% and 30% or about 30%, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30%,by weight, of the composition. In another example, the startingconcentration of the non-polar compound (e.g. active ingredient), or thetotal of all the one or more non-polar compounds, is chosen from withina concentration range of between 1% or about 1% and 50% or about 50%. Inthis example, which typically is used when using more than one non-polaractive ingredient, the total concentration of the non-polar compounds ischosen from within a concentration range of between 30% or about 30% and55% or about 55%, for example between 40% or about 40% and 50% or about50%, by weight, of the composition. Exemplary of starting concentrationsfor individual non-polar active ingredients used in this example arebetween 1% and 50%, for example, 1%, 10.5%, 34%, 45%, by weight of thecomposition, and other concentrations within the range.

In addition to the non-polar compound, the pre-emulsion compositionscontain at least one surfactant. The surfactant has an HLB value ofbetween 14 or about 14 and 20 or about 20, for example, 14, 15, 16, 17,18, 19 or 20, or about 14, about 15, about 16, about 17, about 18, about19, about 20, typically between 16 or about 16 and 18 or about 18.Exemplary of suitable surfactants are tocopherol polyethylene glycolsuccinate (TPGS) and other surfactants having similar properties, forexample, any surfactant having an HLB value between 14 or about 14 and20 or about 20. Surfactants, HLB values, and methods for determining HLBvalues are well known. Typically, the surfactant is a naturalsurfactant, which is safe and/or approved for human consumption.Exemplary of such a natural surfactant is TPGS.

In one example, the starting concentration of the surfactant is greaterthan 50% or about 50%, typically greater than 60% or about 60%,typically greater than 65% or about 65%, for example, greater than 70%or about 70%, for example, a starting concentration within theconcentration range of between 50% or about 50% and 95% or about 95%,between 60% or about 60% and 95% or about 95%, typically between 65% orabout 65% and 90% or about 90%, for example, between 69% or about 69%and 90% or about 90%, for example, between 69% or about 69% and 89% orabout 89%, for example, 65, 66, 67, 68, 69, 69.5, 69.9, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 79.5, 79.9, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 89.5, 89.9, or 90%, by weight, of the composition.

In another example, the starting concentration of the surfactant isgreater than 20% or about 20%, typically greater than 30% or about 30%,for example, between 30% or about 30% and 55% or about 55%, for example,between 30% or about 30% and 50% or about 50%, for example, between 30%or about 30% and 45% or about 45%, for example, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55%, by weight, of the composition. This example is typically usedfor pre-emulsion compositions where the non-polar active ingredientincludes a phytosterol.

One or more, typically more than one, additional ingredients can beadded to the initial pre-emulsion composition. For example, thepre-emulsion compositions typically contain at least one preservative,typically a natural preservative, for example, benzyl alcohol. Exemplaryof other additional ingredients that can be added to the pre-emulsioncompositions, including the initial pre-emulsion compositions, areemulsion stabilizers, for example, a blend of gums; a solvent for thenon-polar compound, for example, an oil other than the non-polarcompound, for example, vitamin E oil or flax seed oil; a pH adjuster,for example, citric acid, or phosphoric acid; one or more flavoringagents, for example, D-limonene or lemon oil; a co-surfactant, forexample, a phospholipid, for example, phosphatidylcholine.

The appropriate concentration ranges for the additional ingredients aredescribed in individual sections below. Typically, the concentration ofthe additional ingredients depends, in part, on the concentrations ofthe non-polar active ingredient and/or of the surfactant. Typically, theconcentrations of these three ingredients are the focus of theformulating methods. For example, when it is determined thatmodifications to ingredient concentrations in the initial pre-emulsioncomposition should be made, it typically is the concentrations of one ormore of these two ingredients that is/are adjusted.

In one example, it can be desirable to add one or more of the additionalingredients after evaluation of the initial pre-emulsion composition,for example, in order to improve the pre-emulsion composition withrespect to one or more desired properties.

ii. Evaluation of the Initial Pre-emulsion Composition

After an initial pre-emulsion composition is made according to themethods provided herein, it is evaluated based on one or more desiredproperties, for example, properties of an aqueous liquid dilutioncomposition containing the diluted pre-emulsion composition, forexample, clarity, color, smell, taste, safety, stability, “ringing” orforming of precipitates and/or the presence of crystals. Typically, theability of the initial pre-emulsion composition to yield a clear (orrelatively clear) liquid dilution composition upon dilution in anaqueous medium is the desired property that is evaluated. In thisexample, the clarity/turbidity of the diluted aqueous liquid dilutioncomposition containing the initial pre-emulsion composition is analyzed.

For evaluation of properties of the aqueous liquid dilution composition,the initial pre-emulsion composition is diluted into an aqueous medium,typically water, for example, at a dilution factor of between 1:10 orabout 1:10 and 1:1000 or about 1:1000, typically between 1:10 or about1:10 and 1:500 or about 1:500, for example, diluted not more than 1:10or about 1:10, at least 1:20 or about 1:20, at least 1:25 or about 1:25,at least 1:50 or about 1:50, at least 1:100 or about 1:100, at least1:200 or about 1:200, at least 1:250 or about 1:250, at least 1:300, atleast 1:400 or at least 1:500, for example, 1:10, 1:20, 1:25, 1:30,1:35, 1:40, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 1:100,1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200,1:210, 1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290,1:300, 1:350, 1:400, 1:450, 1:500. Typically, clarity of the aqueousliquid dilution composition containing the diluted initial pre-emulsioncomposition is evaluated using one or more approaches. Additionally,other properties can be evaluated, for example, smell and/or tasteproperties of the liquid, for example, when the non-polar compound is apolyunsaturated fatty acid (PUFA), particularly fish oil or algae oil,whether the aqueous liquid dilution composition smells “fishy” can beevaluated empirically.

(1) Clarity

In one example, the provided pre-emulsion compositions are formulatedsuch that dilution of the pre-emulsion compositions in aqueous mediumyields clear liquids upon dilution in aqueous medium. To evaluate theclarity of an aqueous liquid dilution composition containing the initialpre-emulsion composition, one of several approaches can be used. Theclarity can be assessed by empirical observation, by measuring particlesize and/or by measuring the turbidity value of the liquid.

In one example, the pre-emulsion compositions formulated such thatdilution of the pre-emulsion compositions in aqueous medium yields clearliquids (or liquids that are equal in clarity to known liquids), byadding between 0.05 grams (g) or about 0.05 g and 10 g or about 10 g ofthe pre-emulsion composition, typically between 0.05 g and 5 g, forexample, 0.05 g, 0.06 g, 0.07 g, 0.08 g, 0.09 g, 0.1 g, 0.2 g, 0.3 g,0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g,7 g, 8 g, 9 g, or 10 g of the pre-emulsion composition, to 8 fluidounces, about 8 fluid ounces, or at least 8 fluid ounces or at leastabout 8 fluid ounces, for example 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 25, 30, 35, 40, 45, 50, 100, 200 or more fluid ounces, ofaqueous medium, for example, water, forming a clear aqueous liquiddilution composition that contains the non-polar compound. In anotherexample, the pre-emulsion composition can be diluted to form a clearaqueous liquid dilution composition by adding between 1 mL or about 1 mLand 10 mL or about 10 mL of the pre-emulsion composition, for example, 1mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL or 10 mL of thepre-emulsion composition to 8 fluid ounces, about 8 fluid ounces, or atleast 8 fluid ounces or at least about 8 fluid ounces, for example 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 100,200 or more fluid ounces, of aqueous medium, for example, water, forminga clear aqueous liquid dilution composition that contains the non-polarcompound.

In another example, the pre-emulsion composition are formulated suchthat dilution of the pre-emulsion compositions in aqueous medium yieldsa clear aqueous liquid dilution composition when at least 25 mg or about25 mg, typically at least 35 mg, for example, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180,190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350,375, 400, 425, 450, 475, 500, 550, 600, 700, 800, 900, 1000, 1500, 2000mg, or more, of the non-polar active ingredient, is contained in atleast 8 fluid ounces or at least about 8 fluid ounces of aqueous liquiddilution composition, for example, a beverage, for example, water.

In another example, the pre-emulsion compositions are formulated suchthat dilution of the pre-emulsion compositions in aqueous medium yieldsa clear aqueous liquid dilution composition at a dilution factor ofbetween 1:10 or about 1:10 and 1:1000 or about 1:1000, typically between1:10 or about 1:10 and 1:500 or about 1:500, for example, when dilutednot more than 1:10 or about 1:10, 1:20 or about 1:20, 1:25 or about1:25, 1:50 or about 1:50, 1:100 or about 1:100, 1:200 or about 1:200,1:250 or about 1:250, 1:300 or about 1:300, 1:400 or about 1:400, 1:500or about 1:500, for example, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:50,1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130,1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230,1:235, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:350, 1:400,1:450, 1:500 or more. In another example, the clear liquid is formed atdilutions less dilute than 1:10 of the pre-emulsion composition.

The provided pre-emulsion compositions can be formulated using anynon-polar compound. In one example, the pre-emulsion compositions can bediluted in aqueous medium, for example, over a wide dilution range toform clear liquids, for example, at a dilution factor of between 1:10 orabout 1:10 and 1:1000 or about 1:1000, typically between 1:10 or about1:10 and 1:500 or about 1:500, for example, when diluted not more than1:10 or about 1:10, 1:20 or about 1:20, 1:25 or about 1:25, 1:50 orabout 1:50, 1:100 or about 1:100, 1:200 or about 1:200, 1:250 or about1:250, 1:300 or about 1:300, 1:400 or about 1:400, 1:500 or about 1:500,for example, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:50, 1:55, 1:60, 1:65,1:70, 1:75, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160,1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:235, 1:240, 1:250,1:260, 1:270, 1:280, 1:290, 1:300, 1:350, 1:400, 1:450, 1:500 or more.Typically, the clarity of the liquid is maintained with increasingdilutions, for example, to infinity.

Clarity of the aqueous liquid dilution composition can be evaluatedusing one of several different approaches, for example, qualitatively,by empirical evaluation, or quantitatively, by measuring particle sizeand/or by measuring the turbidity value of the liquid. In some examples,a particular quantitative or qualitative clarity value is desired. Inanother example, it can be desired that the aqueous liquid dilutioncomposition is as clear as, less clear or more clear than anotherliquid, for example, an aqueous liquid dilution composition madeaccording to the provided methods or a beverage, for example, a beveragethat does not contain the pre-emulsion composition. For example, anaqueous liquid dilution composition, containing the liquid pre-emulsioncomposition diluted in a beverage, can be as clear or about as clear asthe same beverage, containing no pre-emulsion composition. Either typeof evaluation can be done qualitatively, for example by empiricalobservation, or quantitatively, for example, by calculating particlesize and/or turbidity value (NTU) for the liquid(s).

(2) Empirical Evaluation

The relative clarity/turbidity of the aqueous liquid dilutioncomposition containing the diluted initial pre-emulsion composition canbe assessed qualitatively by observation. In one example, a clear liquidis considered clear if it does not have a cloudy appearance and/or if noparticles are visible when looking at the liquid with the naked eye.Clarity can be assessed empirically by comparison to other liquids, forexample, water, fruit juice, soda and/or milk.

In some cases, it is desirable that the liquid be as clear or about asclear as water or another liquid, for example a beverage. For example,it can be desired that the liquid (containing the liquid pre-emulsioncomposition diluted in an aqueous medium, for example, a beverage) is asclear or about as clear as the aqueous medium not containing the liquidpre-emulsion composition. In a related example, it can be desired thatthere is no substantial difference, for example, no observabledifference, between the aqueous liquid dilution composition containingthe pre-emulsion composition and the aqueous medium without thepre-emulsion composition. A clear liquid is not necessarily colorless,for example, a yellow liquid that contains no visible particles orcloudiness can be considered clear.

(3) Particle Size

Alternatively, the clarity of the aqueous liquid dilution compositioncontaining the diluted initial pre-emulsion composition can be assessedby measuring the particle size of the liquid. Methods for measuringparticle size are known. Any method for measuring particle size can beused if it is able to measure particle sizes in the appropriate rangesas described below.

For example, particle size analysis is available commercially, forexample, from Delta Analytical Instruments, Inc. In one example, theparticle size is measured, for example, by Delta Analytical Instruments,Inc., using a light-scattering analyzer, for example, a dynamic lightscattering analyzer, for example, the Horiba® LB-550, which can measureparticle sizes within a range of 0.001 micron to 6 micron and uses aFourier-Transform/Iterative Deconvolution technique for reporting dataand can measure sample concentrations from ppm to 40% solids; theHoriba® LA-920, which is a laser light-scattering instrument having anHe—Ne laser and a tungsten lamp and can determine particle sizes from0.02 micron to 2000 micron using Mie Theory; or other analyzersavailable from Delta Analytical Instruments, Inc.

Alternatively, the particle size can be measured microscopically, forexample, by viewing the liquid under a microscope, for example, at 640×magnification. Using this method, particle size can be quantified bycomparing to a measuring device, for example, a ruler, which is visiblewhen viewing the liquid under the microscope. If any particles areobservable at this magnification, they are measured by comparison to themeasuring device. At a magnification of 640×, for example, any particlethat is about 25 nm, 25 nm, or greater than 25 nm are visible. Particlesizes smaller than 25 nm are not visible at this magnification.

Typically, it is desired that the aqueous liquid dilution compositionshave a particle size less than 200 nm or less than about 200 nm, forexample, 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,150, 160, 170, 180, 190, or 200 nm. Typically, it is desired that theaqueous liquid dilution compositions have a particle size less than 100nm or about 100 nm, less than 50 nm or about 50 nm, or less than 25 nmor about 25 nm. Typically, the particle size of the aqueous liquiddilution composition containing the pre-emulsion composition is between5 nm or about 5 nm and 200 nm or about 200 nm, typically between 5 nm orabout 5 nm and 50 nm or about 50 nm.

(4) Turbidity Measurement

Alternatively, clarity of the liquid can be analyzed by taking anoptical turbidity measurement, which indicates the level of cloudinessor haziness of a liquid, which correlates to size/number of particles insuspension in the liquid. The more clear a particular liquid, the lowerits turbidity value.

Turbidity can measured optically, for example, by using a nephelometer,an instrument with a light and a detector. The nephelometer measuresturbidity by detecting scattered light resulting from exposure of theliquid to an incident light. The amount of scattered light correlates tothe amount of particulate matter in the liquid. For example, a beam oflight will pass through a sample with low turbidity with littledisturbance. Other methods for measuring turbidity are well known andcan be used with the provided methods and compositions.

The units of a turbidity value measured with a nephelometer areNephelomtetric Turbidity Units (NTU). In one example, it is desired thatthe aqueous liquid dilution composition containing the dilutedpre-emulsion composition has low turbidity, for example, a turbidityvalue (NTU) of 30 or about 30; or an NTU value of less than 30 or about30, for example, less than 29 or about 29, less than 28 or about 28,less than 27 or about 27, less than 26 or about 26, less than 25 orabout 25, less than 24 or about 24, less than 23 or about 23, less than22 or about 22, less than 21 or about 21, less than 20 or about 20, lessthan 19 or about 19, less than 18 or about 18, less than 17 or about 17,less than 16 or about 16, less than 15 or about 15, less than 14 orabout 14, less than 13 or about 13, less than 12 or about 12, less than11 or about 11, less than 10 or about 10, less than 9 or about 9, lessthan 8 or about 8, less than 7 or about 7, less than 6 or about 6, lessthan 5 or about 5, less than 4 or about 4, less than 3 or about 3, lessthan 2 or about 2, less than 1 or about 1; or 29 or about 29, 28 orabout 28, 27 or about 27, 26 or about 26, 25 or about 25, 24 or about24, 23 or about 23, 22 or about 22, 21 or about 21, 20 or about 20, 19or about 19, 18 or about 18, 17 or about 17, 16 or about 16, 15 or about15, 14 or about 14, 13 or about 13, 12 or about 12, 11 or about 11, 10or about 10, 9 or about 9, 8 or about 8, 7 or about 7, 6 or about 6, 5or about 5, 4 or about 4, 3 or about 3, 2 or about 2, 1 or about 1, or 0or about 0. In another example, the turbidity value of the aqueousliquid dilution composition is less than 200 or less than about 200, forexample, 200, 175, 150, 100, 50, 25 or less.

In another example, it is desirable that the aqueous liquid dilutioncomposition contains a turbidity value that is comparable, for example,about the same as, the same as, or less than or greater than, theturbidity value of another liquid, for example, a beverage notcontaining the liquid pre-emulsion composition or an aqueous liquiddilution composition made by the provided methods.

iii. Selecting a Formulation and Modifying Formulations

After evaluation of the initial pre-emulsion composition(s), either aparticular formula is chosen or one or more modifications is made to theinitial pre-emulsion composition formula based on the results of theevaluation. When an initial pre-emulsion composition does not displayone or more desired properties, based on the evaluation, theconcentration of one or more ingredients can be adjusted and anotherinitial pre-emulsion composition made, in order to repeat the processuntil a pre-emulsion composition with the desired properties is made.Alternatively, alternative ingredients can be chosen. In one example,modification of the initial pre-emulsion composition involves theaddition of one or more additional ingredients. For example, ifevaluation reveals that the oil and water phases of the aqueous liquiddilution composition containing the diluted pre-emulsion composition areseparating, an emulsion stabilizer can be added to the formulation. Inanother example, a co-surfactant can be added to help emulsify thecomponents of the pre-emulsion composition.

In one example, when evaluation of the initial pre-emulsion compositionreveals that it has desired properties, no modifications are made. Inthis example, the formula of the initial pre-emulsion composition isused for making the pre-emulsion composition. When two or more initialpre-emulsion compositions are made, for example, with increasingconcentrations of an ingredient, the formula of one of the initialpre-emulsion compositions can be chosen. Which formula is chosen can bebased on which formula has the most desirable property. Alternatively,desirable properties can be balanced with relative amounts ofingredients. In one example, it is desirable to choose the formulationthat uses the lowest or the highest concentration of a particularingredient but still provides a pre-emulsion composition that yields aclear liquid upon dilution in an aqueous medium. In one example, thedesired formulation is the formulation that has the lowest concentrationof the surfactant, while still providing a pre-emulsion composition thatyields a clear liquid upon dilution in an aqueous medium. In anotherexample, the desired formulation is the formulation that has the highestconcentration of the non-polar active ingredient, while still providinga pre-emulsion composition that yields a clear liquid upon dilution intoan aqueous medium. In another example, the formulation that yields theclearest liquid is desired.

In another example, however, modifications are made to the formula evenif the initial pre-emulsion composition bears desired properties. Forexample, upon determining that a particular pre-emulsion compositionformulation results in desired properties, it can be desirable to modifythe concentration of one or more ingredients to determine whether thesame desired properties can be achieved if a higher or lowerconcentration of the ingredient(s) is used. For example, it can bedesirable to determine the lowest concentration of surfactant that canbe used, while still generating a pre-emulsion composition with adesired property, for example, the ability to form a clear liquid upondilution in an aqueous medium. In another example, it can be desirableto determine the highest concentration of the non-polar ingredient thatcan be incorporated into a pre-emulsion composition, while stillmaintaining the desired property, for example, the ability of thepre-emulsion composition to form a clear liquid upon dilution in anaqueous medium. In another example, one or more additional ingredientscan be added after making an initial pre-emulsion composition withdesirable properties, for example, flavoring agents and/or pH adjustingagents.

b. Non-Polar Compounds

The pre-emulsion compositions contain one or more non-polar compounds.Non-polar compounds include any lipophilic or lipid soluble compounds,for example, active ingredients, that have greater solubility in organicsolvents (e.g. ethanol, methanol, ethyl ether, acetone, and benzene) andin fats and oils, than in aqueous liquid dilution compositions, forexample, water. Typically, the non-polar compounds used in the providedcompositions are poorly water soluble, for example, water insoluble orcompounds having low water solubility.

Non-polar compounds include drugs, hormones, vitamins, nutrients andother lipophilic compounds. Exemplary non-polar compounds are listedhereinbelow. The provided methods can be used to make pre-emulsioncompositions that can be diluted (e.g. dissolved/dispersed) in aqueousmedium, using any non-polar compound. In one example, the non-polarcompound is not tocopheryl polyethylene glycol succinate (TPGS). Inanother example, the non-polar compound is not Vitamin E. Exemplary ofnon-polar compounds that can be used in the provided pre-emulsioncompositions are:

Non-polar ingredients containing essential fatty acids, for example,polyunsaturated fatty acids (PUFAs), for example, gamma-linolenic acid(GLA), for example, borage oil and evening primrose (Oenothera biennis)oil, blackcurrant seed oil, hemp seed oil, and spirulina extract;compounds containing omega-3 fatty acids, for example, natural andsynthetic omega-3 fatty acids, for example, compounds containing omega-3polyunsaturated long-chain fatty acids, including Eicosapentaenoic acid(EPA) (20:5{acute over (ω)}3); Docosahexaenoic acid (DHA) (22:6{acuteover (ω)}3); Eicosatetraenoic acid (24:4{acute over (ω)}3);Docosapentaenoic acid (DPA, Clupanodonic acid) (22:5{acute over (ω)}3);16:3 {acute over (ω)}3; 24:5 {acute over (ω)}3 and/or nisinic acid(24:6{acute over (ω)}3), for example, fish oil, algae oil, krill oil,canola oil, flaxseed oil, soybean oil and walnut oil; compoundscontaining short-chain omega-3 fatty acids, for example, Alpha-Linolenicacid (α-Linolenic acid; ALA) (18:3{acute over (ω)}3) and Stearidonicacid (18:4{acute over (ω)}3), esters of an omega-3 fatty acid andglycerol, for example, monoglycerides, diglycerides and triglycerides,esters of omega-3 fatty acid and a primary alcohol, for example, fattyacid methyl esters and fatty acid esters, precursors of omega-3 fattyacid oils, for example, EPA precursor, DHA precursor, derivatives suchas polyglycolized derivatives or polyoxyethylene derivatives, oilscontaining the omega-3 fatty acids, for example, fish oil (marine oil),for example, highly pourified fish oil pre-emulsion compositions,perilla oil, krill oil, and algae oil, for example, microalgae oil;compounds containing omega 6 fatty acids, for example, compoundscontaining Linoleic acid (18:2{acute over (ω)}6) (a short-chain fattyacid); Gamma-linolenic acid (GLA) (18:3{acute over (ω)}6); Dihomo gammalinolenic acid (DGLA) (20:3{acute over (ω)}6); Eicosadienoic acid(20:2{acute over (ω)}6); Arachidonic acid (AA) (20:4{acute over (ω)}6);Docosadienoic acid (22:2{acute over (ω)}6); Adrenic acid (22:4{acuteover (ω)}6); and/or Docosapentaenoic acid (22:5{acute over (ω)}6), forexample, borage oil, corn oil, cottonseed oil, grapeseed oil, peanutoil, primrose oil, for example, evening primrose Oenothera biennis) oil,blackcurrant seed oil, hemp seed oil, spurulina extract, safflower oil,sesame oil and soybean oil. Exemplary of a safflower oil that can beused with the provided compositions is the high linoleic safflower oil,distributed by Jedwards, International, Inc., Quincy, MA, whichcontained between 5% and 10% (e.g. 6.65%) C:16 Palmitic acid, between 1%and 3% (e.g. 2.81%) C:18 Stearic acid, between 12% and 18% (e.g. 14.65%)18:1 Oleic acid, between 70% and 80% (e.g. 74.08%) C18:2 Linoleic acidand less than 1% (e.g. 0.10%) C18:3 Linolenic acid;

Other fatty acids, for example, triglycerides, including medium chaintriglycerides, polar lipids, for example, ether lipids, phosphoric acid,choline, fatty acids, glycerol, glycolipids, triglycerides, andphospholipids (e.g., phosphatidylcholine (lecithin),phosphatidylethanolamine, and phosphatidylinositol); saw palmettoextract; and ethyl linoleate; and herb oils, for example, garlic oilsand scordinin; short-chain saturated fatty acids (4:0-10:0), Lauric acid(12:0), Myristic acid (14:0), Pentadecanoic acid (15:0), Palmitic acid(16:0), Palmitoleic acid (16:1 ω7), Heptadecanoic acid (17:0), Stearicacid (18:0), Oleic acid (18:1 ω9), Arachidic acid (20:0);

Micronutrients, for example, vitamins, minerals, co-factors, forexample, Coenzyme Q10 (CoQ10, also called ubiquinone), ubiquinol,tumeric extract (cucuminoids), saw palmetto lipid extract (saw palmettooil), exhinacea extract, hawthorne berry extract, ginseng extract,lipoic acid (thiotic acid), acsorbyl palmitate, kava extract, St. John'sWort (hypericum, Klamath weed, goat weed), extract of quercitin,dihydroepiandrosterone, indol-3-carbinol;

Carotenoids, including hydrocarbons and oxygenated, alcoholicderivatives of hydrocarbons, for example, beta carotene, mixedcarotenoids complex, leutein, lycopene, Zeaxanthin, Cryptoxanthin, forexample, beta-crytoxanthin, astaxanthin, bixin, canthaxanthin,capsanthin, capsorubin, apo-carotenal, beta-12′-apo-carotenal,“Carotene” (mixture of alpha and beta-carotene), gamma carotene,ciolerythrin, esters of hydroxyl- or carboxyl-containing membersthereof;

Fat-soluble vitamins, for example, Vitamins A, D, E and K, andcorresponding provitamins and vitamin derivatives such as esters with anaction resembling that of vitamin A, D, E or K for example; retinol(vitamin A) and pharmaceutically acceptable derivatives thereof, forexample, palmitate ester of retinol and other esters of retinol, andcalciferol (vitamin D) and its pharmaceutically acceptable derivativesthereof and precursors of vitamin D, d-alpha tocopherol (vitamin E) andderivatives thereof, including pharmaceutical derivatives thereof, forexample, Tocotrienols, d-alpha tocopherol acetate and other esters ofd-alpha tocopherol, and ascorbyl palmitate, a fat-soluble version ofvitamin C;

Phytochemicals, including phytoestrogens, for example, genistein anddaidzein, for example, isoflavones, for example, soy isoflavones,flavonoids, phytoalexins, for example, Resveratrol(3,5,4′-trihydroxystilbene), red clover extract, and phytosterols;

Lipid-soluble drugs, including natural and synthetic forms ofimmunosuppressive drugs, such as Cyclosporin, protease inhibitors suchas Ritonavir, macrolide antibiotics and oil soluble anesthetics such asPropofol, natural and synthetic forms of steroidal hormones, forexample, estrogens, estradiols, progesterone, testosterone, cortisone,phytoestrogens, dehydroepinadrosterone (DHEA), growth hormones and otherhormones;

Oil-soluble acids and alcohols, for example, tartaric acid, lactylicacid butylated hydroxyanisole, butylated hydroxytoluene, lignin,sterols, polyphenolic compounds, oryzanol, cholesterol, phytosterols,flavonoids, such as quercetin and reservatol, diallyl disulfides and thelike.

i. Polyunsaturated Fatty Acid (PUFA)-containing Active Ingredients

Exemplary of the non-polar compounds contained in the pre-emulsioncompositions are compounds containing fatty acids, for example, activeingredients containing polyunsaturated fatty acids (PUFAs). Fatty acidsare straight-chain hydrocarbon molecules with a carboxyl (COOH) group atone end of the chain. PUFAs are fatty acids that contain more than onecarbon-carbon double bond in the carbon chain of the fatty acid. PUFAs,particularly essential fatty acids, are useful as dietary supplements.

Different nomenclatures can be used to describe fatty acid molecules.Lipid nomenclature, for example, 18:3 {acute over (ω)}-3, indicates thecarbon chain length, number of double bonds and the position along thecarbon chain of the first carbon-carbon double bond in a fatty acid.Using this nomenclature, each carbon along the chain is labeledaccording to its position relative to one end of the chain. For example,the first carbon away from the carboxylate end is named α, the second isnamed β, and so forth. The last carbon in the molecule (furthest fromthe carboxy group) always is labeled {acute over (ω)} (or omega, or n).The number of carbons and the number of double bonds are listed first inthe lipid name of a fatty acid, separated by a colon. For example, thename “18:3” indicates that the molecule has eighteen (18) carbons andthree (3) double bonds. Following these numbers, the position at whichthe first double bond appears, relative to the last ({acute over (ω)})carbon, is listed. For example, the nomenclature, 18:3 {acute over(ω)}-3 (or 18:3 omega-3; or 18:3 n-3), describes a fatty acid witheighteen (18) carbons and three (3) double bonds, the first of whichoccurs at the third carbon away from the omega carbon.

Alternatively, chemical nomenclature can be used. The chemical name of afatty acid describes the position of each double bond. In the chemicalnaming, the carbons are numbered, beginning with 1, starting with thecarbon that is part of the carboxy (COOH) group. Thus, with thisnumbering system, the α carbon is labeled “2.” The chemical name of thefatty acid lists the first carbon (from the COOH end) to participate ineach double bond.

Certain PUFAs are called essential fatty acids because mammals,including humans, cannot synthesize them using any known chemicalpathway, and must obtain them from diet or by supplementation. (U.S.Pat. No. 6,870,077; Covington, American Family Physician (2004), 70(1):133-140). The essential PUFAs are the omega-3 (6)₃; n-3) fatty acids andthe omega-6 ({acute over (ω)}-6; n-6) fatty acids. Both omega-3 andomega-6 fatty acids are methylene interrupted polyenes, which have twoor more cis double bonds, separated by a single methylene group.Exemplary of Omega-3 fatty acids are Alpha-Linolenic acid (α-Linolenicacid; ALA) (18:3{acute over (ω)}3) (a short-chain fatty acid);Stearidonic acid (18:4{acute over (ω)}3) (a short-chain fatty acid);Eicosapentaenoic acid (EPA) (20:5{acute over (ω)}3); Docosahexaenoicacid (DHA) (22:6{acute over (ω)}3); Eicosatetraenoic acid (24:4{acuteover (ω)}3); Docosapentaenoic acid (DPA, Clupanodonic acid) (22:5{acuteover (ω)}3); 16:3 {acute over (ω)}3; 24:5 {acute over (ω)}3 and nisinicacid (24:6{acute over (ω)}3). Longer chain Omega-3 fatty acids can besynthesized from ALA (the short-chain omega-3 fatty acid). Exemplary ofOmega-6 fatty acids are Linoleic acid (18:2{acute over (ω)}6) (ashort-chain fatty acid); Gamma-linolenic acid (GLA) (18:3{acute over(ω)}6); Dihomo gamma linolenic acid (DGLA) (20:3{acute over (ω)}6);Eicosadienoic acid (20:2{acute over (ω)}6); Arachidonic acid (AA)(20:4{acute over (ω)}6); Docosadienoic acid (22:2{acute over (ω)}6);Adrenic acid (22:4{acute over (ω)}6); and Docosapentaenoic acid(22:5{acute over (ω)}6).

While the longer chain Omega-3 and Omega-6 essential fatty acids can besynthesized from ALA (the short-chain omega-3 fatty acid) and Linolenicacid (LA), respectively, evidence suggests that conversion of theseshort chain fatty acids in humans is slow. Thus, a major source of longchain essential PUFAs is dietary, (see, e.g., Ross et al.,Lipids inHealth and Disease (2007), 6:21; Lands, The FASEB Journal (1992), 6(8):2530). Dietary supplements containing PUFAs, particularly essentialPUFAs, are desirable for protection against cardiovascular disease,inflammation and mental illnesses, (see, e.g., Ross et al., Lipids inHealth and Disease (2007), 6:21; Lands, The FASEB Journal (1992), 6(8):2530; U.S. Pat. No. 6,870,077). Evidence suggests that essential fattyacids, particularly EPA and DHA, in the form of food and nutritionalsupplements, play a role in preventing a number of disease states,including cardiovascular diseases, inflammation, mental health andbehavioral diseases and disorders, (see, e.g., Ross et al.,Lipids inHealth and Disease (2007), 6:21; Lands, The FASEB Journal (1992), 6(8):2530; U.S. Pat. No. 6,870,077; Covington, American Family Physician(2004), 70(1): 133-140).

Omega-9 fatty acids are non-essential PUFAs. Exemplary of omega-9 fattyacids are Oleic acid (which is monounsaturated) (18:1 {acute over(ω)}9); Eicosenoic acid (20:1 {acute over (ω)}9); Mead acid (20:3 {acuteover (ω)}9); Erucic acid (22:1 {acute over (ω)}9); and Nervonic acid(24:1 {acute over (ω)}9).

Conjugated fatty acids are PUFAs with two or more conjugated doublebonds. Conjugated fatty acids can be used as nutritional supplements.Exemplary of conjugated fatty acids are Conjugated Linoleic acid (CLA),for example, 18:2 {acute over (ω)}7, 18:2 {acute over (ω)}6; ConjugatedLinolenic acid, for example, 18:3{acute over (ω)}6, 18:3{acute over(ω)}; and other conjugated fatty acids, for example, 18:3 {acute over(ω)}3, 18:4 {acute over (ω)}3, and 20:5 {acute over (ω)}6.

(1) Omega-3 Fatty Acid Compounds

Exemplary of the PUFA-containing active ingredients that can be used inthe provided compositions are compounds that contain one or more omega-3({acute over (ω)}3; n-3) fatty acids, for example, compounds containingDHA and/or EPA fatty acids, for example, marine oils, for example, fishoil, krill oil and algae oil; and compounds containing ALA fatty acids,for example, flax seed oil.

Typically, oils and aqueous compositions containing long-chainedpolyunsaturated fatty acids (PUFA) are susceptible to oxidation, makingthem unstable and giving them an unpleasant taste. The ingredients andrelative concentrations thereof, as well as the methods for making thepre-emulsion compositions, contribute to desirable properties ofDHA/EPA-containing pre-emulsion compositions. In one example,ingredients and methods minimize the “fishy” odor and/or taste ofDHA/EPA compositions and increase their stability over time. In oneaspect, the compounds in the pre-emulsion compositions have lowoxidation, contributing to these desirable properties.

(a) DHA/EPA

Exemplary of non-polar active ingredients that contain one or moreomega-3 fatty acids, which can be used in the provided compositions, arecompounds containing DHA and/or EPA, for example, marine oil, forexample, fish oil, krill oil and algae oil. Any oil containing DHAand/or EPA can be used. In one example, the non-polar active ingredientcontains between 20% or about 20% and 40% or about 40% DHA. In anotherexample, the non-polar active ingredient contains between 25% or about25% and 35% or about 35% DHA. In another example, the non-polar activeingredient contains at least 70% or about 70%, by weight, DHA, forexample, at least 75% or about 75%, at least 80% or about 80%, at least85% or about 85%, or at least 90% or about 90%, by weight, DHA. Inanother example, the non-polar active ingredient contains between 5% orabout 5% and 15% or about 15% EPA, for example, 5, 6, 7, 8, 9, 10, 11,12, 13, 14 or 15%, by weight, EPA. In another example, the non-polaractive ingredient contains not more than 10% or about 10% EPA or lessthan 10% or about 10%, EPA. In another example, the non-polar activeingredient contains DHA and EPA, for example, DHA representing at least20% or about 20%, by weight of the non-polar active ingredient and EPArepresenting not more than 13% or about 13% of the non-polar activeingredient, for example, not more than 10% or about 10%, by weight ofthe non-polar active ingredient. In another example, the non-polaractive ingredient contains DHA, representing at least 35% or about 35%of the non-polar active ingredient and EPA representing not more than13% or about 13% of the non-polar active ingredient, for example, notmore than 10% or about 10% of the non-polar active ingredient. Inanother example, the non-polar active ingredient contains DHA and EPA,for example, DHA representing at least 70% or about 70% of the non-polaractive ingredient and EPA representing not more than 13% or about 13% ofthe non-polar active ingredient, for example, not more than 10% or about10% of the non-polar active ingredient.

(i) Fish Oils

Exemplary of the PUFA-containing non-polar active ingredients that canbe used in the provided compositions are oils derived from fish, whichcontain DHA, EPA or both DHA and EPA. Particularly, cold water marinefish are a known source of Omega-3 fatty acids (U.S. Pat. No.4,670,285). Suitable fish oil containing DHA, EPA or both DHA and EPAcan be obtained from any of a number of commercial sources, for example,fish oils available from Jedwards International, Inc., any of which canbe used with the provided compositions.

Fish oils typically are extracted from fish tissue, for example, frozenfish tissue. In one example, the fish oil is a tasteless fish oil, forexample, a cod liver oil, which has been isolated from fish, forexample, from cod liver, and then refined and deodorized, or in someother way treated so its taste becomes neutral, for example, asdescribed in International Publication Nos. WO 00/23545 and WO2004/098311. In one example, these fish oils are isolated from frozenfish tissue by a process that minimizes oxidation. Exemplary of such atasteless fish oil is Denomega™ 100, Borregaard Ingredients, Sarpsborg,Norway; distributed by Denomega Nutritional Oils AS, Boulder, Colo.Typically, the tasteless fish oil, for example, cod liver oil, containsbetween 25% or about 25% and 35% or about 35% Omega-3 fatty acids, forexample, 34% Omega-3 fatty acids. In one example, the fish oil, forexample, the Denomega™ 100 oil, contains 13% or about 13% DHA and 13% orabout 13% EPA.

Also exemplary of the fish oils that can be included in the providedcompositions are fish oils containing high amounts of Omega-3 fattyacids, for example, high amounts of DHA. One example of such a fish oilcontains at least about 85% DHA, typically greater than 85% DHA and atleast about 90% Omega-3 fatty acids, typically greater than, 90% Omega-3fatty acids. In another example, the fish oil can contain 98% PUFA, 89%Omega-3 fatty acids, about 70% DHA, about 10% EPA, 8.9% Omega-6 fattyacids and 0.7% Omega-9 fatty acids.

Exemplary of a fish oil containing high amounts of Omega-3 fatty acidsthat can used as the non-polar compound in the provided compositions isan Omega-3 Fish Oil EE (O3C Nutraceuticals, supplied by JedwardsInternational Inc., Quincy, Mass.), which contains 89% Omega-3 fattyacids, 8.9% Omega-6 fatty acids, 0.7% Omega-9 fatty acids, 0.1%saturated fatty acids, 1.0% monounsaturated fatty acids, 74.5%Docosahexanoic (DHA) fatty acids, 9.3% Eicosapentaenoic (EPA) fattyacids and 98% polyunsaturated fatty acids (PUFA). This fish oil alsocontains 0.1% (16:0) palmitic acid, 0.1% (16:1 {acute over (ω)}7)palmitoleic acid, 0.1% (18:0) stearic acid, 0.6% (18:1 {acute over(ω)}9) oleic acid, 0.1% (18:1 {acute over (ω)}7) oleic acid, 0.3% (18:2{acute over (ω)}6) linoleic acid, 0.2% (18:3 {acute over (ω)}3)linolenic acid, 0.2% (18:4 {acute over (ω)}3) octadecatetraenoic acid,0.1% (20:1 {acute over (ω)}9) eicosanoic acid, 0.1% (20:2 {acute over(ω)}6) eicosadienoic acid, 0.2% (20:3 {acute over (ω)}6) EicosatrienoicAcid, 2.4% (20:4 {acute over (ω)}6) arachidonic acid, 0.6% (20:4 {acuteover (ω)}3) arachidonic acid, 0.1% (22:1 {acute over (ω)}11) erucicacid, 0.6% (21:5 {acute over (ω)}3) uncosapentaenoic acid, 0.5% (22:4{acute over (ω)}6) docosatetraenoic acid, 5.4% (22:5 {acute over (ω)}6)docosapentaenoic acid, 3.6% (22:5 {acute over (ω)}3) docosapentaenoicacid and 0.9% other fatty acids.

Also exemplary of a fish oil containing high amounts of Omega-3 fattyacids that can be used in the provided compositions is OmegaPre-emulsion composition 85 DHA TG Ultra (O3C Nutraceuticals AS, Oslo,Norway), which contains greater than 85% DHA (C22:6n-3) and greater than90% total omega-3 fatty acids and is isolated from fatty fish speciesEugraulidae, Clupeidae and Scombridae families. This fish oil isproduced by purifying and concentrating the oils from these fish withgentle technologies to increase the concentration of omega-3 fatty acidDHA. Any fish oil containing DHA and/or EPA can be used as the non-polarcompound in the provided compositions. Also exemplary of the fish oilsare other fish oils made by O3C Nutraceuticals, AS and other fish oilssupplied by Jedwards, International, Inc.

Also exemplary of the fish oils are krill oils, made according toInternational Publication No. WO 2007/080515.

(ii) Algae Oil

Also exemplary of non-polar compounds containing Omega-3 PUFAs,particularly DHA (and optionally EPA), that can be used as the non-polarcompound in the provided compositions are oils derived frommicroorganisms, for example, oils derived from marine dinoflagellates,for example, microalgae, for example, Crypthecodinium sp, particularly,Crypthecodinium cohnii. Microalgae oils, like fish oil, are an excellentsource of omega-3 fatty acids, particularly DHA (U.S. Pat. Nos.5,397,591, 5,407,957, 5,492,938 and 5,711,983). Exemplary of oilsderived from microalgae are the oils disclosed in (and oils madeaccording to the methods described in) U.S. Pat. Nos. 5,397,591,5,407,957, 5,492,938 and 5,711,983 and U.S. Publication number2007/0166411, including DHASCO® and DHASCO-S® (Martek BiosciencesCorporation).

Also exemplary of non-polar compounds containing Omega-3 PUFAs,particularly DHA (and optionally EPA), that can be used as the non-polarcompound in the provided compositions are oils derived frommicroorganisms, for example, oils derived from marine dinoflagellates,for example, microalgae, for example, Crypthecodinium sp, particularly,Crypthecodinium cohnii. Microalgae oils, like fish oil, are an excellentsource of omega-3 fatty acids, particularly DHA (U.S. Pat. Nos.5,397,591, 5,407,957, 5,492,938 and 5,711,983). Exemplary of oilsderived from microalgae are the oils disclosed in (and oils madeaccording to the methods described in) U.S. Pat. Nos. 5,397,591,5,407,957, 5,492,938 and 5,711,983 and U.S. Publication number2007/0166411, including DHASCO® and DHASCO-S® (Martek BiosciencesCorporation).

For example, U.S. Pat. No. 5,397,591 describes, inter alia, single celledible oils (algae oils) (and methods for making the oils), whichcontain at least 70% triglycerides, which contain about 20-35% DHA andlack EPA, isolated from Crypthecodinium cohnii, preferably containingmore than 70% triglycerides, having 15-20% myristic acid; 20-25%palmitic acid; 10-15% oleic acid; 30-40% DHA and 0-10% othertriglycerides. U.S. Pat. No. 5,407,957 describes, inter alia, algae oils(and methods for making the oils) derived from Crypthecodinium cohnii,preferably containing greater than about 90% triglycerides, at least 35%DHA by weight, in one example, having 15-20 myristic acid, 20-25%palmitic acid, 10-15% oleic acid, 40-45% DHA, and 0-5% other oils. U.S.Pat No. 5,492,938 describes, inter alia, single cell edible oils (andmethods for making the oils) containing at least 70% triglycerides,which contain about 20-35% DHA and lack EPA, isolated fromCrypthecodinium cohnii, in one example containing more than 70%triglycerides, having 15-20% myristic acid; 20-25% palmitic acid; 10-15%oleic acid; 30-40% DHA; 0-10% other triglycerides. U.S. Pat. No.5,711,983 describes, inter alia, single cell edible oils (and methodsfor making the oils) containing at least 70% triglycerides, whichcontain about 20-35% DHA and lack EPA, isolated from Crypthecodiniumcohnii, in one example, containing more than 70% triglycerides, having15-20% myristic acid; 20-25% palmitic acid; 10-15% oleic acid; 30-40%DHA and 0-10% other triglycerides.

Also exemplary of suitable microalgae oils are those disclosed, forexample, in U.S. Pat. No. 6,977,166 and U.S. Publication No.2004/0072330. Any oil derived from dinoflagellates, for example,microalgae, which contains DHA, and optionally EPA, is suitable as analgae oil for use with the provided compositions, for example, V-Purealgae oil (Water4Life, Switzerland, which contains EPA and DHA).

(b) Flax Seed Oil-omega 3 (ALA)

Also exemplary of the Omega-3 containing non-polar compounds used in theprovided compositions is flaxseed oil (flaxseed oil, linseed oil).Flaxseed oils, which are good sources of omega-3 fatty acids,particularly alpha-linolenic acid, have been used as nutritionalsupplements. Flaxseed oils are produced by pressing the flax seed andrefining the oil from the flax seeds. Exemplary of flaxseed oil that canbe used as the non-polar compound in the provided compositions isflaxseed oil derived from Linum usitatissimum L., for example, flaxseedoil supplied by Sanmark LLC, Greensboro, N.C. (Sanmark Limited, Dalian,Liaoning Province, China), which contains not less than (NLT) 50% C18:3alpha-linolenic acid, and further contains other fatty acids, forexample, 3-8% C16:0 Palmitic acid, 2-8% C18:0 Stearic acid, 11-24% C18:1Oleic acid, 11-24% C18:2 linoleic acid and 0-3% other fatty acids. Alsoexemplary of suitable flaxseed oil is a flaxseed oil containing 6%Palmitic acid, 2.5% stearic acid, 0.5% arachidic acid, 19% oleic acid,24.1% linoleic acid, 47.4 linolenic acid, and 0.5% other fatty acids.The fatty acid composition of flaxseed oil can vary. Any flaxseed oilcan be used as the non-polar compound in the provided compositions. Inone example, the flaxseed oil contains at least 50% alpha-linolenic acidor at least about 50% alpha-linolenic acid. In another example, theflaxseed oil contains at least 65% or 70% alpha-linolenic acid or atleast about 65% or about 70% alpha-linolenic acid. Exemplary of aflaxseed containing greater than 65% linolenic acid content (of totalfatty acid content), for example, 70-80% or 70-75%, is the flaxseeddescribed in U.S. Pat. No. 6,870,077.

(2) Omega-6 Compounds

Also exemplary of the non-polar compounds used in the providedcompositions are compounds containing omega-6 PUFAs, for example,gamma-linolenic acid (GLA), for example, borage oil and evening primrose(Oenothera biennis) oil, blackcurrant seed oil, hemp seed oil, fungaloil and spirulina extract. Any oil containing omega-6 fatty acids can beused in the provided compositions.

(a) Borage Oil (Gamma-Linolenic Acid (GLA))

Exemplary of the omega-6 containing non-polar compounds are compoundscontaining GLA, for example, borage oil. GLA is an omega-6 PUFA, whichprimarily is derived from vegetable oils, for example, evening primrose(Oenothera biennis) oil, blackcurrant seed oil, hemp seed oil, andspirulina extract. GLA has been used as a nutritional supplement. It hasbeen proposed that GLA has a role in treating various chronic diseasesand in particular that it has anti-inflammatory effects (Fan and ChapkinThe Journal of Nutrition (1998), 1411-1414). In one example, thenon-polar active ingredient contains at least about 22% or about 22%, byweight, GLA, for example, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 50, 60, or more, %, by weight, GLA.

Borage (Borago officinalis), also known as “starflower” is an herb withseeds containing high amounts of GLA. Exemplary of borage oil that isused as a non-polar active ingredient in the provided compositions isthe borage oil supplied by Sanmark LLC, Greensboro, N.C. (SanmarkLimited, Dalian, Liaoning Province, China), derived by pressing andisolating oil from the seeds of Borago officinalis L. This oil containsnot less than (NLT) 22% C18:3 gamma-linolenic acid (GLA), between 9 and12% C16:0 Palmitic acid, between 3 and 5% C18:0 Stearic acid, between 15and 20% C18:1 Oleic acid, between 35 and 42% C18:2 linoleic acid,between 3 and 5% C20:1 Ocosenoic acid, between 1 and 4% C22:1 Docosenoicacid and between 0 and 4% other fatty acids. Other borage oils can beused. Other GLA-containing oils also can be used as the non-polarcompound.

(3) Saw Palmetto Extract

Also exemplary of the non-polar compounds used in the providedcompositions is saw palmetto extract, a lipophilic extract of the ripeberries of the American dwarf palm (also called Serenoa repens or Sabalserrulata), which has been used to treat genitourinary and otherdiseases and to enhance sperm production, breast size and libido, as amild diuretic, a nerve sedative, an expectorant and a digestive tracttonic, and particularly to treat benign prostate hyperplasia (BHP)(Ernst, Academia and Clinic (2002), 136; 42-53; Gordon and Shaughnessy,Complementary and Alternative Medicine (2003), 76(6); 1281-1283). Sawpalmetto extract is commercially available from a number of sources. Anysaw palmetto lipid extract can be used in the provided compositions.Exemplary of the saw palmetto extract that can be used in the providedcompositions is Saw Palmetto, Lipophilic Extract, commercially availablefrom Natural Medicinals, Inc., Felda, Fla. This Saw Palmetto LipophilicExtract is Carbon Dioxide extracted and, in one example, contains, 85.9%total fatty acids, including 0.8% Caproic acid, 2% Caprylic acid, 2.4%Capric acid, 27.1 Lauric acid, 10.3 Myristic acid, 8.1% Palmitic acid,0.2% Palmitoleic acid, 2% Stearic acid, 26.7 Oleic acid, 4.9% Linoleicacid, 0.7% linolenic acid, 0.42%; 0.42% phytosterols, including 0.42%beta Sitosterol, 0.09% Campesterol, 0.03% Stigmasterol; and 0.2%moisture. Other sources of saw palmetto extract can be used.

(4) Conjugated Linoleic Acid (CLA)

Also exemplary of the PUFA non-polar compounds that can be used in theprovided compositions are non-polar compounds containing conjugatedfatty acids. Conjugated fatty acids are PUFAs with two or moreconjugated double bonds. Conjugated fatty acids can be used asnutritional supplements. Exemplary of the active ingredients containingconjugated fatty acids are compounds containing Conjugated Linoleic acid(CLA), for example, 18:2 {acute over (ω)}7, 18:2 {acute over (ω)}6;Conjugated Linolenic acid, for example, 18:3{acute over (ω)}6,18:3{acute over (ω)}5; and other conjugated fatty acids, for example,18:3 {acute over (ω)}3, 18:4 {acute over (ω)}3, and 20:5 {acute over(ω)}6. CLA refers to a family of linoleic acid isomers found primarilyin meat and dairy products of ruminants. Typically, the CLA compoundscontain a mixture of different CLA isomers, for example, C18:2 CLA c9,t11, CLA t10, c12 and other CLA isomers. Exemplary of the CLA that canbe used as an active ingredient in the provided compositions is CLA(80%) commercially available from Sanmark, LTD (Dalian, LiaoningProvince, China; product code 01057-A80). This CLA is clear white topale yellow oil and has the following fatty acid composition: NMT (notmore than) 9.0% C16:0 Palmitic acid, NMT 4.0% Stearic acid, NMT 15.0%C18:1 Oleic acid, NMT 3.0% C18:2 Linoleic acid, NLT (not less than) 80%C18:2 CLA (including the following isomers: NLT 37.5% C18:2 CLA c9, t11,37.5% C18:2 CLA t10, c12, and NMT 5.0% other CLA isomers); and NMT 5.0%other fatty acids. Other CLA containing compounds can be used.

ii. Coenzyme Q Active Ingredients

Exemplary of the non-polar active ingredients are compounds containingCoenzyme Q, for example, Coenzyme Q10 (also called CoQ10, ubiquinone,ubidicarenone, ubiquinol and vitamin Q10). Coenzyme Q compounds arebenzoquinone compounds containing isoprenyl units. The number ofisoprenyl units in each of the different CoQ species is indicated with anumber following CoQ. For example, CoQ10 contains 10 isoprenyl units.Coenzyme Q10 is a predominant Coenzyme Q species.

Coenzyme Q can exist in two different forms: an oxidized form and areduced form. When the oxidized form of a Coenzyme Q species is reducedby one equivalent, it becomes a ubisemiquinone, denoted QH, whichcontains a free radical on one of the oxygens in the benzene ring of thebenzoquinone. Both oxidized and reduced coenzyme Q containing compoundscan be used as active ingredients in the provided compositions.

(1) Coenzyme Q10

Exemplary of the Coenzyme Q containing non-polar active ingredients thatcan be used in the provided compositions are active ingredientscontaining Coenzyme Q10. Coenzyme Q10 (also called CoQ10, ubiquinone,ubidicarenone, ubiquinol, and vitamin Q10) is a benzoquinone compoundthat contains 10 isoprenoid units. The “Q” in the name refers to Quinoneand the 10 refers to the number of isoprenoid units. CoQ10 typicallyrefers to the oxidized form of CoQ10, which also is referred to asubidicarenone, as opposed to the reduced form of CoQ10. In both thereduced and oxidized CoQ10 are exemplary of the coenzyme Q species thatcan be used as active ingredients in the provided compositions.

CoQ10 has electron-transfer ability and is present in cellularmembranes, such as those of the endoplasmic reticulum, peroxisomes,lysosomes, vesicles and the mitochondria. A decrease in natural CoQ10synthesis has been observed in sick and elderly people. Because of thisobservation and its potent antioxidant properties, CoQ10 is used as adietary supplement and a treatment for diseases such as cancer and heartdisease. CoQ10, however, exhibits relatively poor bioavailability.

CoQ10 containing compounds are available commercially. Any CoQ10compound or reduced CoQ10 compound can be used with the providedcomposition. Exemplary of the CoQ10 compounds that can be used as activeingredients are coenzyme Q10 compounds containing greater than 98% orgreater than about 98% ubidicarenone, for example, the compound soldunder the name Kaneka Q10™ (USP Ubidicarenone) by Kaneka Nutrients,L.P., Pasadena, Tex. The compound sold under the name Kaneka Q10™ isfermented entirely from yeast and is identical to the body's own CoQ10and free from the cis isomer found in some synthetically produced CoQ10compounds. Any CoQ10 compound can be used in the provided compositions.

iii. Phytosterol-Containing Active Ingredients

Exemplary of the non-polar compounds used as active ingredients in theprovided compositions are phytosterol (plant sterol)-containingcompounds. Plant sterols are structurally similar to cholesterol andhave been found to reduce the absorption of dietary cholesterol, whichcan affect the levels of serum cholesterol. According to the U.S. Foodand Drug Administration (FDA), two servings per day, each containing 0.4grams of plant sterols, for a total daily intake of at least 0.8 grams,as part of a diet low in saturated fat and cholesterol, can reduce therisk of heart disease. Thus, plant sterols are used in nutritionalsupplements.

Any phytosterol-containing compound can be used as an active ingredientin the provided compositions. Exemplary of the phytosterol-containingcompounds that can be used as active ingredients in the providedcompositions are compounds containing plant sterols, for example, thecompound sold under the name CardioAid™, distributed by B&D Nutritionand manufactured by ADM Natural Health and Nutrition, Decatur, Ill. Thiscompound contains Kosher, Pareve, and Halal plant sterols that areproduced under current food GMPs. The sterols are PCR negative and thematerial is derived from genetically modified organisms (GMOs). Thisphytosterol compound contains a minimum of 95% plant sterols, which caninclude up to 5 plant sterols. The compound can contain, for example,40-58% Beta sitosterol, 20-30% Campesterol, 14-22% Stigmasterol, 0-6%Brassicasterol and 0-5% Sitostanol. The compound further can containtocopherols, for example, 0-15 mg/g tocopherols. The compound is testedand is negative for Salmonella, E. coli and Staphylococcus aureus.

c. Other Components of the Pre-emulsion Compositions i. Surfactants

In addition to the one or more non-polar compound(s), each of theprovided compositions contains at least one surfactant. In one example,the compositions contain one or more additional surfactants, which arereferred to as co-surfactants or emulsifiers.

Surfactants (and co-surfactants) are molecules that contain bothhydrophobic and hydrophilic portions. In one example, the hydrophobicportion is a hydrophobic tail and the hydrophilic portion is ahydrophilic head of the surfactant molecule.

Exemplary of surfactants that can be used in the provided methods andcompositions are surfactants having an HLB value of between 14 or about14 and 20 or about 20, typically between 16 or about 16 and 18 or about18. Exemplary of suitable surfactants include, but are not limited to,Vitamin E-derived surfactants, such as tocopherol and/ortocotrienol-derived surfactants, in which the Vitamin E moietyrepresents the hydrophobic region of the surfactant, and is attached,via a linker, to another moiety, such as a polyethylene glycol (PEG)moiety, that provides the hydrophilic portion of the surfactant.Vitamin-E derived surfactants include, but are not limited to,tocopherol derived surfactants, including polyalkylene glycolderivatives of tocopherol, typically polyethylene glycol (PEG)derivatives of tocopherol, such as tocopherol polyethylene glycolsuccinate (TPGS), TPGS analogs, TPGS homologs and TPGS derivatives.Alternatively, the surfactants can be other PEG derivatives havingsimilar properties, for example, PEG derivatives of sterols, e.g. acholesterol or a sitosterol (including, for example, any of the PEGderivatives disclosed in U.S. Pat. No. 6,632,443) or PEG-derivatives ofother fat-soluble vitamins, for example, some forms of Vitamin A (e.g.Retinol) or Vitamin D (e.g. Vitamin D1-D5).

In the provided compositions, the surfactants aggregate in aqueousliquid dilution compositions to form micelles, which contain thenon-polar compound(s). The hydrophilic portion(s) of the surfactantmolecules are oriented toward the outside of the micelle, in contactwith the aqueous medium, while the hydrophobic portion(s) of thesurfactant molecules are oriented toward the center of the micelle, incontact with the non-polar compound(s), which is contained in the centerof the micelle. The micelles can contain more than one surfactant.

In general, surfactants also are capable of forming “inverse micelles,”which form in lipophilic medium, the hydrophobic tails being in contactwith the lipophilic medium and the hydrophilic heads facing the centerof the inverse micelle. Typically, however, the surfactants in theprovided compositions form micelles in aqueous medium, for example, inaqueous liquids, containing the non-polar ingredient at their center.

Properties of the provided compositions, for example, the particle sizeof the compositions and desirable properties related to the particlesize, are influenced by the choice of surfactant(s) and the relativeamount (concentration) of surfactant. For example, the HLB of thesurfactant(s) can affect particle size, clarity, taste, smell, crystalformation and other properties of the provided compositions. Similarly,the concentration of the surfactant compared with the concentration(s)of other ingredients, particularly compared with the concentration ofwater and the concentration of the non-polar compound(s), can affectvarious desirable properties, for example, the ability to disperse ordissolve in aqueous media, for example, to form a clear aqueous liquiddilution composition or pleasant taste and/or smell.

ii. PEG-Derivatives of Vitamin E

Typically, the surfactant used in the provided compositions and methodsis a Vitamin E-derived surfactant (e.g. a tocopherol-derived or atocotrienol-derived surfactant). Exemplary of suitable Vitamin E-derivedsurfactants are polyalkylene glycol derivatives, typically polyethyleneglycol (PEG) derivatives, of Vitamin E, for example, PEG derivatives oftocopherol. Suitable PEG derivatives of Vitamin E typically contain oneor more tocopherols or tocotrienols, joined (for example, by an ester,ether, amide or thioester bond) with one or more PEG moieties, via alinker, for example, a dicarboxylic acid linker. An exemplary surfactantis shown schematically below:

where the line between the PEG and Linker; and the line between theLinker and Vitamin E each independently represent a covalent bondselected from among an ester, ether, amide or thioester.

Typically, the Vitamin E PEG derivatives are made by joining the PEGmoiety, via esterification, to a vitamin E-linker conjugate (e.g. atocopherol-linker conjugate). In one example, the tocopherol-linkerconjugate first is formed by covalently joining (by esterification) thehydroxyl moiety of tocopherol with a dicarboxylic acid to produce anester bond. In this example, the tocopherol-linker conjugate is atocopherol ester (such as tocopherol succinate). The esterificationreaction can be carried out by any of a number of known methods (see,for example, U.S. Pat. Nos. 2,680,749, 4,665,204, 3,538,119 and6,632,443). To make the tocopherol-PEG surfactant, the resultingtocopherol ester then is joined (via the linker) to the PEG molecule, inanother esterification reaction. In this example, the resultingsurfactant is a tocopherol polyethylene glycol diester (TPGD).

Alternatively, PEG derivatives of a tocopherol-linker ortocotrienol-linker conjugate can be made by other methods. Variousmethods known in the art for producing PEG derivatives can be used tojoin a PEG molecule to tocopherol-linker or tocotrienol-linkercompounds. For example, a tocopherol-linker conjugate can be covalentlybonded to the PEG molecule via an amide, ether or thioether bond. Forexample, a tocopherol-linker conjugate that contains an amine group canbe reacted with a PEG-NHS derivative to form an amide bond between thetocopherol-linker and the PEG molecule. A tocopherol-linker conjugatethat contains an amine group can be reacted with a PEG-aldehydederivative to form an amide bond between the tocopherol-linker and thePEG molecule. In another example, a tocopherol-linker that contains ancarboxylic acid can be activated to the corresponding acid halide andreacted with a PEG-SH derivative to form a thioester bond between thetocopherol-linker and the PEG molecule.

(1) Tocopherols and Tocotrienols

The tocopherol(s) used to make the surfactant can be any natural orsynthetic Vitamin E tocopherol, including but not limited toalpha-tocopherols, beta-tocopherols, gamma-tocopherols and deltatocopherols, either in pure forms or in heterogenous mixtures of morethan one form. Exemplary tocopherols are d- α tocopherols andd,1-tocopherols. To make the surfactant, the tocopherol typically isesterified with a linker, for example, a dicarboxylic acid, to form atocopherol ester, which then is joined to a PEG moiety.

The tocotrienol(s) used to make the surfactants can be any natural orsynthetic Vitamin E tocotrienol, including but not limited toalpha-tocotrienols, beta-tocotrienols, gamma-trienols and deltatocotrienols, either in pure forms or in heterogenous mixtures of morethan one form. Mixtures of tocopherols and tocotrienols, arecontemplated for use in the provided methods and compositions. Atocotrienol can be esterified with a linker, such as a dicarboxylicacid, before joining with a PEG moiety.

(2) PEG Moieties

The PEG used in the tocopherol-PEG derivative can be any of a pluralityof known PEG moieties. Exemplary of suitable PEG moieties are PEGmoieties having varying chain lengths, and varying molecular weights,for example, PEG 1000, PEG 200, PEG 500, and PEG 20,000. The numbersfollowing individual PEG moieties indicate the molecular weight (indaltons (Da)) of the PEG moieties. The PEG moiety of thetocopherol-derived surfactant typically has a molecular weight ofbetween 200 or about 200 to 20,000 or about 20,000 Da, typically between200 and 6000 Da, for example, between 600 or about 600 Da and 6000 orabout 6000 Da, typically between 200 or about 200 Da and 2000 or about2000 Da, between 600 or about 600 Da and 1500 or about 1500 Da 200, 300,400, 500, 600, 800, and 1000 Da. Exemplary of a PEG-derivative oftocopherol ester having a PEG moiety with 1000 Da is TPGS-1000. Alsoexemplary of suitable PEG moieties are PEG moieties that are modified,for example, methylated PEG (m-PEG), which is a PEG chain capped with amethyl group. Other known PEG analogs also can be used. The PEG moietiescan be selected from among any reactive PEG, including, but not limitedto, PEG-OH, PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH₂, PEG-CO₂H, andbranched PEGs.

(3) Linkers

Typically, the PEG derivatives of Vitamin E are diesters or otheresters, e.g. triesters. When the PEG derivative is a diester, the linkerjoining the Vitamin E to the PEG typically is a carboxylic acid,typically a dicarboxylic acid, as in, for example, tocopherolpolyethylene glycol succinate (TPGS), where the linker is a succinicacid, and the surfactant is made by an esterification reaction joining aPEG moiety and a tocopherol ester of the dicarboxylic acid. In anotherexample, the linker is another molecule, for example, an amino acid,such as glycine, alanine, 5-aminopentanoic acid or 8-aminooctanoic acid;or an amino alcohol, such as ethanolamine.

(4) Tocopherol Polyethylene Glycol and Tocotrienol Polyethylene GlycolDiesters (Dicarboxylic Acid Esters of Vitamin E Linked to PEG)

Typically, the Vitamin E PEG derivatives are vitamin E polyethyleneglycol diesters, which are Vitamin E esters of PEG, made by joining aVitamin E ester to one or more PEG moieties by esterification. Exemplaryof the Vitamin E diesters are tocopherol polyethylene glycol diesters(TPGD) and tocotrienol polyethylene glycol diesters.

When the tocopherol or tocotrienol ester linked with the PEG moiety is atocopherol ester of a dicarboxylic acid (e.g. tocopherol succinate), thelinker is a dicarboxylic acid (a carboxylic acid having two carboxygroups, e.g. succinic acid). In this example, the tocopherol ortocotrienol PEG diester is formed by esterification reaction, in whichPEG is attached to a tocopherol ester of a dicarboxylic acid.

Exemplary of dicarboxylic acids that can be used as linkers in thesetocopherol and tocotrienol PEG diester surfactants are succinic acid,sebacic acid, dodecanodioic acid, suberic acid, or azelaic acid,citraconic acid, methylcitraconic acid, itaconic acid, maleic acid,glutaric acid, glutaconic acid, fumaric acids and phthalic acids.Accordingly, exemplary of the tocopherol esters that can be esterifiedto form the PEG-derivatives are tocopherol succinate, tocopherolsebacate, tocopherol dodecanodioate, tocopherol suberate, tocopherolazelaate, tocopherol citraconate, tocopherol methylcitraconate,tocopherol itaconate, tocopherol maleate, tocopherol glutarate,tocopherol glutaconate, and tocopherol phthalate, among others.

Exemplary of the vitamin E polyethylene glycol diesters made withdicarboxylic acids are compounds having the following formula shown inscheme I below (and homologs, analogs and derivatives thereof):

where R¹, R², R³ and R⁴ each independently is H or Me; each dashed lineis independently a single or double bond; n is an integer from 1-5000; mand q each independently are 0 or 1; and p is an integer from 1-20. Inone example, the surfactant is a compound where, when both m and q are0, p is an integer between 2-20.

In one example, the surfactant has the following formula shown in SchemeII below (including homologs, analogs and derivatives thereof):

where when R ¹, R², R³ and R⁴ represent a hydrogen or methyl, the bondrepresented by the dashed line is either a single or double bond, m isany integer between 1 and 20, and n=1-5000.

Exemplary of tocopherol and tocotrienol PEG diesters that can be used assurfactants in the provided compositions and methods include, but arenot limited to: tocopherol polyethylene glycol succinates (TPGS;including d-αTPGS and d,1 -TPGS; see for example, U.S. Pat. No.3,102,078), tocophyrol polyethylene glycol sebacate (PTS; see forexample, U.S. Pat. No. 6,632,443), tocopherol polyethylene glycoldodecanodioate (PTD; see for example, U.S. Pat. No. 6,632,443),tocopherol polyethylene glycol suberate (PTSr; see for example, U.S.Pat. No. 6,632,443) and tocopherol polyethylene glycol azelaate (PTAz;see for example, U.S. Pat. No. 6,632,443), polyoxyethanyl tocotrienylsebacate (PTrienS, for example, PTrienS-600; see for example, U.S. Pat.No. 6,632,443), as well as analogs, homologs and derivatives or any ofthe tocopherol diesters.

(5) Other Vitamin E PEG Esters

In another example, the tocopherol ester joined to the PEG to form thetocopherol PEG diester is a tocopherol ester of a tricarboxylic acid,for example, Citric acid, Isocitric acid, Aconitic acid andPropane-1,2,3-tricarboxylic acid (tricarballylic acid, carballylic acid)or a carboxylic acid having three or more carboxy groups.

In another example, the PEG derivatives of tocopherol are tocopherolpolyethylene glycol triesters (TPGT), for example, esters containing atocopherol, a linker, a PEG moiety, and an additional moiety, forexample, an additional tocopherol, a second PEG moiety, or awater-soluble group, such as a quaternary amine. In one example, whenthe triester contains two PEG moieties, each PEG moiety has a smallerchain length (and lower molecular weight) than the PEG moiety in a PEGderivative of tocopherol, having similar properties, that contains onlyone PEG chain.

(a) TPGS Surfactants

Exemplary of the tocopherol polyethylene glycol diester surfactants areTPGS, and analogs, homologs and derivatives thereof. TPGS is a naturalsurfactant that is GRAS and Kosher certified and thus, desirable for usein products designated for human consumptions, for example, beverages,food and nutritional supplements. TPGS typically has an HLB value ofbetween 16 or about 16 and 18 or about 18. Exemplary of the TPGSsurfactants is TPGS-1000, which has a PEG moiety of 1000 Da. Exemplaryof the TPGS surfactants that can be used in the provided compositions isthe food grade TPGS surfactant sold under the name Eastman Vitamin ETPGS®, food grade, by Eastman Chemical Company, Kingsport, TN. Thissurfactant is a water-soluble form of natural-source vitamin E, which isprepared by esterifyifig the carboxyl group of crystallined-alpha-tocopheryl acid succinate with polyethylene glycol 1000 (PEG1000), and contains between 260 and 300 mg/g total tocopherol. A similarcompound can be made by esterifying the carboxyl group of the d,1 formof synthetic Vitamin E with PEG 1000. It forms a clear liquid whendissolved 20% in water. This tocopheryl polyethylene glycol is awater-soluble preparation of a fat-soluble vitamin (vitamin E), forexample, as disclosed in U.S. Pat. Nos. 3,102,078 and 2,680,749 and U.S.Published Application Nos. 2007/0184117 and 2007/0141203. The PEG moietyof alternative TPGS surfactants can have a molecular weight range ofabout 200 or 200 to 20,000 or about 20,000 Da, for example, between 600or about 600 Da and 6000 or about 6000 Da, typically between 600 orabout 600 Da and 1500 or about 1500 Da. Also exemplary of the TPGSsurfactant that can be used in the provided compositions is the WaterSoluble Natural Vitamin E (TPGS), sold by ZMC-USA, The Woodlands, Texas.Any known source of TPGS, or any analog, homolog or derivative thereof,can be used.

Exemplary of TPGS analogs are compounds, other than TPGS, that aresimilar to a parent TPGS compound, but differ slightly in composition,for example, by the variation, addition or removal of an atom, one ormore units (e.g. methylene unit(s)—(CH₂)_(n)) or one or more functionalgroups.

At room temperature, TPGS typically is a waxy low-melting solid. In oneexample, the TPGS is heated prior to use, for example, to at least themelting temperature, for example, between 37° C. or about 37° C. and 41°C. or about 41° C. and the desired amount is poured out. In anotherexample, the TPGS can be added as a waxy solid to a vessel and heatedwith the heating apparatus.

Also exemplary of the surfactants are TPGS analogs, which includeVitamin E derived surfactants, including PEG derivatives of Vitamin E,including vitamin E PEG diesters, such as, but not limited to,tocophyrol polyethylene glycol sebacate (PTS), tocopherol polyethyleneglycol dodecanodioate (PTD), tocopherol polyethylene glycol suberate(PTSr), tocopherol polyethylene glycol azelaate (PTAz) andpolyoxyethanyl tocotrienyl sebacate (PTrienS) as well as other PEGderivatives of Vitamin E.

iii. Concentration of the Surfactant

Typically, the concentration of the surfactant(s) in a particularpre-emulsion composition is selected, as described hereinabove, byformulating an initial pre-emulsion composition with a surfactant(s)concentration within a starting concentration range, followed byevaluation of the initial pre-emulsion composition and, optionally,adjusting the surfactant(s) concentration. Alternatively, the surfactantconcentration can be chosen based on the concentration of surfactant inone or more existing liquid pre-emulsion composition formula.

In one example, the concentration of the surfactant is greater than 50%or about 50%, typically greater than 60% or about 60%, typically greaterthan 65% or about 65%, for example, greater than 70% or about 70%, forexample, a starting concentration within the concentration range ofbetween 50% or about 50% and 95% or about 95%, between 60% or about 60%and 95% or about 95%, typically between 65% or about 65% and 90% orabout 90%, for example, between 69% or about 69% and 90% or about 90%,for example, between 69% or about 69% and 89% or about 89%, for example,65, 66, 67, 68, 69, 69.5, 69.9, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,79.5, 79.9, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 89.5, 89.9, or 90%,by weight, of the composition.

In another example, the concentration of the surfactant is greater than20% or about 20%, typically greater than 30% or about 30%, for example,between 30% or about 30% and 55% or about 55%, for example, between 30%or about 30% and 50% or about 50%, for example, between 30% or about 30%and 45% or about 45%, for example, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55%, byweight, of the composition. This example is typically used forpre-emulsion compositions where the non-polar active ingredient includesa phytosterol.

iv. HLB

Exemplary of the properties of the surfactant(s) that contribute to thedesirable properties of the compositions is the HLBhydrophilic-lipophilic balance) of the surfactant(s). Generally, HLB isa value, derived from a semi-empirical formula, which is used to indexsurfactants according to their relative hydrophobicity/hydrophilicity.An HLB value is a numerical representation of the relativerepresentation of hydrophilic groups and hydrophobic groups in asurfactant or mixture of surfactants. The weight percent of theserespective groups indicates properties of the molecular structure. See,for example, Griffin, W.C. J. Soc. Cos. Chem. 1:311 (1949).

Surfactant HLB values range from 1-45, while the range for non-ionicsurfactants typically is from 1-20. The more lipophilic a surfactant is,the lower its HLB value. Conversely, the more hydrophilic a surfactantis, the higher its HLB value. lipophilic surfactants have greatersolubility in oil and lipophilic substances, while hydrophilicsurfactants dissolve more easily in aqueous liquids. In general,surfactants with HLB values greater than 10 or greater than about 10 arecalled “hydrophilic surfactants,” while surfactants having HLB valuesless than 10 or less than about 10 are referred to as “hydrophobicsurfactants.” HLB values are known for a number of surfactants Table 1lists HLB values of exemplary surfactants and co-surfactants.

The surfactant(s) used in the provided pre-emulsion compositiontypically has an HLB value between 14 or about 14 and 20 or about 20,for example, 14, 15, 16, 17, 18, 19, 20, about 14, about 15, about 16,about 17, about 18, about 19 or about 20. Exemplary of suitablesurfactants is tocopherol polyethylene glycol succinate (TPGS; alsocalled tocopheryl polyethylene glycol succinate). Other knownsurfactants having HLB values between 14 or about 14 and 20 or about 20also can be suitable. Typically, the surfactant is a natural surfactant,for example, a surfactant that is GRAS (generally recognized as safe) bythe FDA and/or Kosher certified, for example, TPGS.

(1) TPGS

Exemplary of a surfactant having an HLB between 14 or about 14 and 20 orabout 20 is tocopherol polyethylene glycol succinate (TPGS), a naturalsurfactant that is GRAS and Kosher certified and thus, desirable for usein products designated for human consumption, for example, beverages,food and nutritional supplements. TPGS typically has an HLB value ofbetween 16 or about 16 and 18 or about 18.

Exemplary of the TPGS surfactants that can be used in the providedcompositions is the food grade TPGS surfactant sold under the nameEastman Vitamin E TPGS®, food grade, by Eastman Chemical Company,Kingsport, TN. This surfactant is a water-soluble form of natural-sourcevitamin E, which is prepared by esterifying the carboxyl group ofcrystalline d-alpha-tocopheryl acid succinate with polyethylene glycol1000 (PEG 1000), and contains between 260 and 300 mg/g total tocopherol.A similar compound can be made by esterifying the carboxyl group of thed,1 form of synthetic Vitamin E with PEG 1000. It forms a clear liquidwhen dissolved 20% in water. This tocopheryl polyethylene glycol is awater-soluble preparation of a fat-soluble vitamin (vitamin E), forexample, as disclosed in U.S. Pat. Nos. 3,102,078 and 2,680,749 and U.S.Published Application Nos. 2007/0184117 and 2007/0141203. The PEG moietyof alternative TPGS surfactants can have a molecular weight range ofabout 200 or 200 to 20,000 or about 20,000 Da. Also exemplary of theTPGS surfactant that can be used in the provided compositions is theWater Soluble Natural Vitamin E (TPGS), sold by ZMC-USA, The Woodlands,Texas. Any known source of TPGS can be used.

At room temperature, TPGS typically is a waxy low-melting solid. In oneexample, the TPGS is heated prior to use, for example, to at least themelting temperature, for example, between 37° C. or about 37° C. and 41°C. or about 41° C. and the desired amount is poured out. In anotherexample, the TPGS can be added as a waxy solid to a vessel and heatedwith the heating apparatus.

(2) Co-surfactants (Emulsifiers)

In one example, the liquid pre-emulsion composition further contains oneor more co-surfactants (emulsifiers). For example, a co-surfactant canbe included to improve emulsification of the active ingredient and/orthe stability of the composition, for example, by preventing or slowingoxidation of the non-polar compound. Exemplary of a co-surfactant usedin the provided pre-emulsion compositions is a phospholipid, forexample, phosphatidylcholine.

(a) Phospholipids

Exemplary of the co-surfactants that can be used in the providedcompositions are phospholipids. Phospholipids are amphipathic lipid-likemolecules, typically containing a hydrophobic portion at one end of themolecule and a hydrophilic portion at the other end of the molecule. Anumber of phospholipids can be used as ingredients in the providedcompositions, for example, lecithin, including phosphatidylcholine (PC),phosphatidylethanolamine (PE), distearoylphosphatidylcholine (DSPC),phosphatidylserine (PS), phosphatidtylglycerol (PG), phosphatidic acid(PA), phosphatidylinositol (PI), sphingomyelin (SPM) or a combinationthereof. Typically, the phospholipid is phosphatidylcholine (PC), whichsometimes is referred to by the general name “lecithin.” Exemplary ofthe phospholipids that can be used as co-surfactants in the providedcompositions are the phospholipids sold by Lipoid, LLC, Newark, N.J.,for example, Purified Egg Lecithins, Purified Soybean Lecithins,Hydrogenated Egg and Soybean Lecithins, Egg Phospholipids, SoybeanPhospholipids, Hydrogenated Egg and Soybean Phospholipids. SyntheticPhospholipids, PEG-ylated Phospholipids and phospholipid blends sold byLipoid, LLC. Exemplary of the phosphatidylcholine that can be used as aco-surfactant in the provided compositions is the phosphatidylcholinecomposition sold by Lipoid, LLC, under the name Lipoid S100, which isderived from soy extract and contains greater than 95% or greater thanabout 95% phosphatidylcholine.

In one example, the phospholipid, for example, PC, represents less thanor equal to 1% or about 1%, by weight (w/w) of the pre-emulsioncomposition. In one example, the phosphatidylcholine represents between0.1% or about 0.1% and 1% or about 1%, for example, 0.1, 0.15, 0.2,0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.65, 0.66, 0.6690, 0.7, 0.75,0.8, 0.85, 0.9, 0.95 or 1%, per weight (w/w), of the pre-emulsioncomposition. In one example, the phospholipid represents between 0.15%or about 0.15% and 0.7% or about 0.7%, by weight (w/w) of thepre-emulsion composition.

v. Preservatives and Sterilizers

In one example, the provided liquid pre-emulsion composition furthercontains one or more preservatives (or preservativers) and/orsterilizers. The preservative(s) can be included to improve thestability of the pre-emulsion composition, and the compositions made bydiluting the pre-emulsion composition, over time. Preservatives,particularly food and beverage preservatives, are well known. Any knownpreservative can be used in the provided compositions. Exemplary of thepreservatives that can be used in the provided compositions are oilsoluble preservatives, for example, benzyl alcohol, Benzyl Benzoate,Methyl Paraben, Propyl Paraben, antioxidants, for example, Vitamin E,Vitamin A Palmitate and Beta Carotene. Typically, a preservative isselected that is safe for human consumption, for example, in foods andbeverages, for example, a GRAS certified and/or Kosher-certifiedpreservative, for example, benzyl alcohol.

The preservative typically represents less than 1%, less than about 1%,1% or about 1%, by weight (w/w), of the pre-emulsion composition orbetween 0.1% or about 0.1% and 1% or about 1%, by weight, of thepre-emulsion composition, for example, 0.1%, 0.2%, 0.3%, 0.4%,0.5%,0.6%, 0.7%, 0.725%, 0.75%, 0.8%, 0.9%, 1%, about 0.1%, about 0.2%, about0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about0.9%, about 1%, by weight (w/w), of the liquid pre-emulsion composition.

vi. Emulsion Stabilizers (Co-Emulsifier)

In one example, the provided liquid pre-emulsion compositions furthercontain one or more emulsion stabilizers (co-emulsifiers), which can beused to stabilize the pre-emulsion composition and/or the aqueouscompositions containing the diluted pre-emulsion compositions. In oneexample, the emulsion stabilizer increases the viscosity of the liquidpre-emulsion composition. In one example, one or more emulsionstabilizers is added, during formulation, after evaluation of an initialpre-emulsion composition, particularly if the oil and water phases ofthe aqueous liquid dilution composition resulting from dilution of theinitial pre-emulsion composition appear to be separating. Addition ofthe emulsion stabilizer can prevent separation of the oil and waterphases, for example, in the liquid dilution compositions.

Exemplary of an emulsion stabilizer that can be used in the providedcompositions is a composition containing a blend of gums, for example,gums used as emulsifying agents, for example, a blend containing one ormore of xanthan gum, guar gum and sodium alginate, for example, theemulsion stabilizer sold under the brand name SALADIZER®, available fromTIC Gums, Inc. (Belcamp, Md.). Other gums can be included in theemulsion stabilizer, for example, gum acacia and sugar beet pectin.Other blends of similar gums can also be used as emulsion stabilizers.

In one example, the emulsion stabilizer is added at a concentration thatis less than 1%, for example, between 0.01% or about 0.01% and 1% orabout 1% (w/w), emulsion stabilizer, for example, 0.01%, 0.02%, 0.03%,0.04%, 0.05%, 0.06%, 0.061%, 0.062%,0.063%, 0.0635%, 0.07%, 0.08%,0.09%, 0.1%, 0.12%, 0.13%, 0.14%, 0.15%,0.16%, 0.17%, 0.18%, 0.19%,0.2%, 0.25%, 0.3%, 0.31%, 0.32%, 0.33%,0.34%, 0.35%, 0.36%, 0.37%,0.38%, 0.39%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%, by weight (w/w),of the liquid pre-emulsion composition.

vii. Solvents

In one example, the liquid pre-emulsion compositions further contain asolvent, for example, an oil. Typically, the solvent is included in thecomposition in addition to the non-polar active ingredient, and is usedto dissolve the non-polar active ingredient. In one example, the solventis an oil that is not contained in the non-polar active ingredient.Typically, the solvent is not the non-polar active ingredient. A numberof ingredients can be used either as solvents or as non-polar compounds.When a solvent is included in the pre-emulsion composition, it typicallyis used to dissolve the non-polar compound before mixing with the otheringredients. In one example, use of a solvent reduces the crystal sizeand/or increase the clarity of the aqueous liquid dilution compositioncontaining the diluted pre-emulsion composition. Exemplary of solventsthat can be used in the provided pre-emulsion compositions are oils (inaddition to the non-polar active ingredient), for example, Vitamin Eoil, flaxseed oil, CLA, Borage Oil, D-limonene, Canola oil, corn oil,MCT oil and oat oil. Other oils also can be used. Exemplary of theVitamin E oil, used as a solvent in the provided compositions, is theoil sold by ADM Natural Health and Nutrition, Decatur, Ill, under thename Novatol™ 5-67 Vitamin E (D-alpha-Tocopherol; ADM product code410217). This Vitamin E oil contains at least 67.2% Tocopherol andapproximately 32.8% soybean oil. Also exemplary of a suitable solvent issafflower oil, for example, the high linoleic safflower oil, distributedby Jedwards, International, Inc., Quincy, Mass., which contained between5% and 10% (e.g. 6.65%) C:16 Palmitic acid, between 1% and 3% (e.g.2.81%) C:18 Stearic acid, between 12% and 18% (e.g. 14.65%) 18:1 Oleicacid, between 70% and 80% (e.g. 74.08%) C18:2 Linoleic acid and lessthan 1% (e.g. 0.10%) C18:3 Linolenic acid.

In one example, the concentration of the solvent is within aconcentration range of between 1% or about 1% and 55% or about 55%, forexample, 1%, 2%, 3%,3.25%,3.5%,3.75%,4%,5%,5.25%,5.5% or 5.75%,10, 11,12, 13, 14, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, or more, %, by weight, of the pre-emulsion composition.

viii. Flavors

In one example, the pre-emulsion composition further contains one ormore flavors or flavoring agents, for example, any compound to addflavor to the pre-emulsion composition and/or to the aqueous liquiddilution composition containing the diluted pre-emulsion composition,for example, the food or beverage containing the pre-emulsioncomposition. Several flavors are well known. Any flavor can be added tothe pre-emulsion compositions, for example, any flavor sold by MissionFlavors, Foothill Ranch, Calif. Exemplary of flavors that can be usedare fruit flavors, such as guava, kiwi, peach, mango, papaya, pineapple,banana, strawberry, raspberry, blueberry, orange, grapefruit, tangerine,lemon, lime, lemon-lime, etc.; cola flavors, tea flavors, coffeeflavors, chocolate flavors, dairy flavors, root beer and birch beerflavors, methyl slicylate (wintergreen oil, sweet birch oil), citrusoils and other flavors. Typically, the flavors are safe and/or desirablefor human consumption, for example, GRAS or Kosher-certified flavors.Exemplary of flavoring agents that can be used in the compositions arelemon oil, for example lemon oil sold by Mission Flavors, FoothillRanch, Calif.; and D-limonene, for example, 99% GRAS certifiedD-Limonene, sold by Florida Chemical, Winter Haven, Fla. Typically, theconcentration of flavoring agent added to the provided pre-emulsioncompositions is less than 5% or about 5%, typically less than 1% orabout 1%, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%,0.9%, 0.37% or 0.525%, by weight (w/w), of the pre-emulsion composition.

ix. pH Adjusters

In one example, one or more pH adjusters is added to the providedpre-emulsion compositions. Alternatively, the pH adjuster can be added,at an appropriate concentration to achieve a desired pH. Typically, thepH adjuster is added to adjust the pH of the pre-emulsion composition towithin a range of 2.0 or about 2.0 to 4.0 or about 4.0. One or more of aplurality of pH adjusting agents can be used. Typically, the pHadjusting agent is safe for human consumption, for example, GRAScertified. Exemplary of the pH adjuster is citric acid, for example, thecitric acid sold by Mitsubishi Chemical, Dublin, Ohio.

Typically, the concentration of pH adjuster added to the providedpre-emulsion compositions is less than 5% or about 5%, typically lessthan 1% or about 1%, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%,0.7%, 0.8%, 0.9%, 0.28% or 0.19%, by weight (w/w), of the pre-emulsioncomposition.

2. Powder

The compositions also can be provided in powder form, i.e. powder thatis made by converting the provided pre-emulsion composition into apowder, using one of several well-known methods (e.g. spray-dryingand/or milling). The powder compositions include, but are not limitedto, coated or uncoated swallowable or chewable tablets, dry powders inhard or soft gelatin capsules, and dry powders in individual or multipleuse packages for reconstituted suspensions or sprinkles. Preferablesolid dosage forms are coated or uncoated swallowable or chewabletablets. Suitable methods for manufacturing the powder compositions arewell known in the art.

Additionally, the powder composition can further contain at least oneexcipient. For example, the powder can be formed by spray-drying apre-emulsion composition that has been mixed with one or moreexcipients. Excipients include, but are not limited to, diluents(sometimes referred to as fillers) including, for example,microcrystalline cellulose, mannitol, lactose, calcium phosphate,dextrates, maltodextrin, starch, sucrose, and pregelatinized starch;disintegrants including, for example, crospovidone, sodium starchglycolate, croscarmellose sodium, starch, pregelatinized starch, andcarboxymethylcellulose sodium; binders including, for example, starch,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pregelatinizedstarch, guar gum, alginic acid, gum acacia, carboxymethylcellulosesodium, and polyvinyl pyrrolidone; glidants including, for example,colloidal silicon dioxide and talc; and lubricants/antiadherentsincluding, for example, magnesium stearate, calcium stearate, stearicacid, sodium stearyl fumarate, glyceryl monostearate, hydrogenatedvegetable oil, and talc. In one particular example, the excipients areselected from any one or more of maltodextrin and gum acacia. In oneexample, the excipient contains a 35:65 ratio of maltodextrin:gumacacia. In another example, the excipient is maltodextrin.

Typically, the concentration of the excipients is within a concentrationrange of between 50% or about 50% and 85% or about 85%, for example, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 ormore, %, by weight, of the free flowing powder.

The powder forms can be used for any convenient dosage amount thenon-polar compound. Generally, the level of non-polar compound can beincreased or decreased according to the judgment of the physician,pharmacist, pharmaceutical scientist, or other person of skill in theart. The amount of the remaining non-active ingredients can be adjustedas needed.

In one example, the powder form is a free-flowing powder. Free-flowingpowders can be obtained using techniques well known in the art, such as,but not limited to, spray drying, freeze drying or absorption plating.In one example, in order to achieve a free flowing powder, the proteinderivative is formulated with an excipient such as lactose or starch.For example, the formulation can be a spray-dried lactose formulation(see e.g., U.S. Pat. No. 4,916,163).

The methods for forming the powders include spray drying. Spray-dryingprocesses and spray-drying equipment are described generally in Perry'sChemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition 1984).More details on spray-drying processes and equipment are reviewed byMarshall, “Atomization and Spray-Drying,” 50. Chem. Eng. Prog. Monogr.Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition1985). Methods for spray drying are well known (see, e.g. U.S. Pat. Nos.5,430,021; 6,534,085 and U.S. application publication numberUS2007/0184117). In general, spray drying is used to dry a heated liquidby passing it through hot gas. One or more spray nozzles is used toatomize the liquid in a cooling tower or chamber. As the material isatomized (sprayed), the surface tension causes a uniform sphericalparticle to form, which is passed through the cooling chamber andhardens into a solid intact sphere. The spray dried particles can bebetween at or about 0.5 microns and at or about 100 microns, andtypically are less than at or about 10 microns, typically less than ator about 5 microns, and typically less than at or about, or at or about,1 micron.

Provided are methods for spray drying the pre-emulsion compositions toform powder compositions. In the spray drying methods, the pre-emulsioncompositions are heated, e.g. to a temperature between at or about 100and at or about 150° F., typically between 110° F. and 140° F., e.g. ator about 110, 115, 120, 125, 130, 135 or 140° F. The compositions can bemixed while heating, such as with any of the mixers described herein,for example, homogenizers (e.g. reversible homogenizers andpiston-driven homogenization homogenizers).

For spray-drying, one or more excipients are mixed with a polar solvent,typically water, and heated, e.g. to a temperature between at or about100° F. and at or about 150° F., typically between 110° F. and 140° F.,e.g. at or about 110, 115, 120, 125, 130, 135 or 140° F. In one example,the excipient is mixed with water in an amount of one part excipient (byweight) to two parts water (by weight). The excipient-solvent (e.g.water) mixture can be mixed while heating, e.g. using any of the mixersdescribed herein, for example, homogenizers (e.g. reversiblehomogenizers and piston-driven homogenizers) with heating during themixing. The heated pre-emulsion composition and the heatedwater-excipient mixture then are mixed together, such as by transferringone mixture to the other, e.g. by any of the transfer means providedherein. Typically, the two mixtures are homogenized, e.g. with areversible homogenizer or piston-driven homogenizer or any otherhomogenizer. The homogenized mixture then is subject to spray dryingusing a spray dryer.

Exemplary of the spray dryers are cyclone spray dryers. During spraydrying with cyclone spray dryers, the homogenized mixture is pumped intoan atomizing device where it is broken into small droplets. Upon contactwith a stream of hot air, the moisture is removed very rapidly from thedroplets while still suspended in the drying air. The dry powder isseparated from the moist air in cyclones by centrifugal action. Thecentrifugal action is caused by the great increase in air speed when themixture of particles and air enters the cyclone system. The dense powderparticles are forced toward the cyclone walls while the lighter, moistair is directed away through the exhaust pipes. The powder settles tothe bottom of the cyclone where it is removed through a dischargingdevice. Sometimes the air-conveying ducts for the dry powder areconnected with cooling systems which admit cold air for transport of theproduct through conveying pipes. Cyclone dryers have been designed forlarge production schedules capable of drying ton-lots of powder perhour.

As will be appreciated by one of skill in the art, the inlet temperatureand the outlet temperature of the spray drier are not critical but willbe of such a level to provide the desired particle size, of less than ator about 1 micron, and to result in a powder that has a desiredproperty. Typically, the ability of the free flowing powder to yield aclear (or relatively clear) liquid dilution composition upon dilution inan aqueous medium is the desired property that is evaluated. In thisregard, the inlet and outlet temperatures are adjust depending on themelting characteristics of the pre-emulsion concentrate components andthe composition of the homogenized pre-emulsion concentrate/excipientmixture. The inlet temperature is between at or about 60° C. and at orabout 170° C. with outlet temperatures between at or about 40° C. to ator about 120° C. Preferably inlet temperatures are from at or about 90°C. to at or about 120° C. and outlet temperatures are from at or about60° C. to at or about 90° C. The flow rate which is used in the spraydrying equipment will generally be at or about 3 mL per minute to at orabout 15 mL per minute. The atomizer air flow rate will very betweenvalues of at or about 25 L per minute to at or about 50 L per minute.Commercially available spray dryers are well known to those of skill inthe art, and suitable settings for any particular dispersion can bereadily determined by one of skill in the art without undueexperimentation. Operating conditions such as inlet temperature andoutlet temperature, feed rate, atomization pressure, flow rate of thedrying air, and nozzle configuration can be adjusted in accordance withthe manufacturer's guidelines.

In some examples, the dry powder is stored into a capsule form or ispressed into a tablet. For use as tablets, the compositions typicallycontain multiple other excipients. These excipients include tabletdisintegrants, such as corn starch, glidants, such as silicon dioxide,and lubricants such as magnesium stearate. Ordinarily these compositionscontain minor amounts by weight of glidants and lubricants, e.g., eachtwo percent (2%) or less by weight. Tablet disintegrants are optionallypresent, and, if present, are included in sufficient amounts to assurethat the tablet disintegrates upon ingestion. According materials, suchas corn starch, are employed at concentrations of from about zero toabout 30 percent by weight of the composition.

Free flowing powders also can be used to administer the active agent byinhalation using a dry powder inhaler. Such dry powder inhalerstypically administer the active agent as a free-flowing powder that isdispersed in a patient's air-stream during inspiration. In order toachieve a free flowing powder, the active agent is typically formulatedwith a suitable excipient such as lactose or starch. For example, such adry powder formulation can be made, for example, by combining thelactose with the active agent and then dry blending the components.Alternatively, if desired, the active agent can be formulated without anexcipient. The pharmaceutical composition is then typically loaded intoa dry powder dispenser, or into inhalation cartridges or capsules foruse with a dry powder delivery device. Examples of dry powder inhalerdelivery devices include Diskhaler (GlaxoSmithKline, Research TrianglePark, N.C.) (see, e.g., U.S. Pat. No. 5,035,237); Diskus(GlaxoSmithKline) (see, e.g., U.S. Pat. No. 6,378,519); Turbuhaler(AstraZeneca, Wilmington, Del.) (see, e.g., U.S. Pat. No. 4,524,769);Rotahaler (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 4,353,365) andHandihaler (Boehringer Ingelheim). Further examples of suitable DPIdevices are described in U.S. Pat. Nos. 5,415,162, 5,239,993, and5,715,810 and references cited therein.

3. Liquid Dilution Compositions Containing the Diluted Pre-emulsionCompositions

Also among the compositions provided herein are liquid dilutioncompositions, typically aqueous liquid dilution compositions, containingthe non-polar compounds. The aqueous liquid dilution compositions aremade by diluting the provided pre-emulsion compositions into aqueousmedia, for example, beverages, for example, water, flavored water, soda,milk, coffee, tea, juices, including fruit juices, sauces, syrups,soups, sports drinks, nutritional beverages, energy drinks,vitamin-fortified beverages, or any beverage.

In one example, the aqueous liquid dilution compositions containsbetween 0.05 grams (g) or about 0.05 g and 10 g or about 10 g, typicallybetween 0.05 g and 5 g, of the liquid pre-emulsion composition per 8fluid ounces or about 8 fluid ounces, at least 8 fluid ounces or atleast about 8 fluid ounces, or less than 8 fluid ounces or less thanabout 8 fluid ounces, or per serving size, of the aqueous medium, forexample, 0.05 g, 0.06 g, 0.07 g, 0.08 g, 0.09 g, 0.1 g, 0.2 g, 0.3 g,0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g,7 g, 8 g, 9 g, or 10 g of the pre-emulsion composition per 8 fluidounces, about 8 fluid ounces, or at least 8 fluid ounces or at leastabout 8 fluid ounces of the aqueous medium, for example 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 100, 200 ormore fluid ounces, of aqueous medium.

In another example, the aqueous liquid dilution composition containsbetween 1 mL or about 1 mL and 10 mL or about 10 mL of the liquidpre-emulsion composition, for example, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6mL, 7 mL, 8 mL, 9 mL or 10 mL of the pre-emulsion composition, per 8fluid ounces, about 8 fluid ounces, at least 8 fluid ounces or at leastabout 8 fluid ounces, or less than 8 fluid ounces or less than about 8fluid ounces, or per serving size, of the aqueous medium, for example 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50,100, 200 or more fluid ounces, of aqueous medium.

In another example, the aqueous liquid dilution composition contains atleast 10 mg or about 10 mg, typically at least 25 mg or about 25 mg,typically at least 35 mg, of the non-polar compound, for example, thenon-polar active ingredient, per 8 fluid ounces or about 8 fluid ounces,at least 8 fluid ounces or at least about 8 fluid ounces of the aqueousmedium, or less than 8 ounces or less than about 8 ounces, or perserving size, of the aqueous medium; for example, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110,120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250,260, 270, 280, 290, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550,600, 700, 800, 900, 1000, 1500, 2000 mg, or more, of the non-polarcompound per at least 8 fluid ounces or at least about 8 fluid ounces ofaqueous medium.

In another example, the aqueous liquid dilution composition contains thepre-emulsion composition diluted at a dilution factor of between 1:10 orabout 1:10 and 1:1000 or about 1:1000 or more, typically between 1:10 orabout 1:10 and 1:500 or about 1:500 or more, for example, diluted notmore than 1:10 or about 1:10, 1:20 or about 1:20, 1:25 or about 1:25,1:50 or about 1:50, 1:100 or about 1:100, 1:200 or about 1:200, 1:250 orabout 1:250, 1:300 or about 1:300, 1:400 or about 1:400, 1:500 or about1:500, for example, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:50, 1:55,1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140,1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:235,1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:350, 1:400, 1:450,1:500 or more. In another example, the aqueous liquid dilutioncompositions contain the liquid pre-emulsion composition diluted to anyamount. In another example the dilution is less than 1:10 or about 1:10.

Properties of the provided liquid pre-emulsion compositions that arediluted into the aqueous medium contribute to various properties of theprovided resulting aqueous liquid dilution compositions, for example,clarity; desirability for human consumption, for example, pleasanttaste, and/or smell, for example, lack of “fishy” taste/smell, lack of“ringing” and lack of crystal formation; stability, for example, lack ofoxidation, “ringing” and/or precipitation over time; and safety forhuman consumption. As described above, the liquid pre-emulsioncompositions are formulated according to the desired properties of theaqueous liquid dilution compositions containing the pre-emulsioncompositions.

a. Clarity

In one example, the aqueous liquid dilution compositions are clearaqueous liquid dilution compositions or non-turbid aqueous liquiddilution compositions, for example, as determined, as described below,empirically or by measuring turbidity and/or particle size. In anotherexample, the aqueous liquid dilution compositions are not clear, or notcompletely clear. The liquids can be more or less clear, or have thesame clarity as another liquid, for example, an aqueous liquid dilutioncomposition made according to the provided methods or a beverage, forexample, a beverage that does not contain the diluted pre-emulsioncomposition. Properties of the liquid pre-emulsion compositions canaffect the clarity of the liquid. A number of parameters can vary theclarity of the liquids, for example, the relative concentration ofsurfactant, non-polar compound and/or water; the type of non-polaringredient; the concentration of excipient(s) in the particularnon-polar compound; and the purity of the non-polar compound, forexample, whether it has been standardized to a high purity, or whetherit is an extract or a filtered extract. For example, an aqueous liquiddilution composition made by diluting a pre-emulsion compositioncontaining a non-polar active ingredient that contains lecithin, forexample a high amount of lecithin, can be less clear than one made witha pre-emulsion composition containing a non-polar compound that does notcontain lecithin. In another example, a liquid pre-emulsion compositioncontaining a non-polar compound that is a filtered extract can produce aclearer aqueous liquid dilution composition when diluted than apre-emulsion composition containing a crude extract.

i. Clarity Determined by Empirical Evaluation

In one example, the clarity/turbidity of the aqueous liquid dilutioncomposition containing the diluted pre-emulsion composition is evaluatedqualitatively, by observation. In one example, a liquid can beconsidered clear if it does not have a cloudy appearance and/or if no orfew particles are visible when viewing the liquid with the naked eye orif it is the same or substantially similar in clarity to another liquid,for example, a beverage, for example, water, fruit juice, soda or milk.In some cases, the aqueous liquid dilution composition is as clear orabout as clear as water or another liquid, for example a beverage. Forexample, the liquid (containing the liquid pre-emulsion compositiondiluted in an aqueous medium, for example, a beverage) can be as clearor about as clear as the aqueous medium not containing the liquidpre-emulsion composition. In a related example, there is no substantialdifference, for example, no observable difference, between the aqueousliquid dilution composition containing the pre-emulsion composition andthe aqueous medium without the pre-emulsion composition. A clear liquidis not necessarily colorless, for example, a yellow liquid that containsno visible particles or cloudiness can be considered clear. In anotherexample, the liquid is clear or partially clear or substantially clearif no crystals are visible and/or if no “ringing” is observed on thecontainer containing the liquid.

ii. Clarity Determined by Particle Size or Number of Particles

In another example, clarity of the aqueous liquid dilution compositionis evaluated by measuring the particle size and/or number of particlesof the liquid.

In one example, the aqueous liquid dilution compositions have a particlesize less than 200 nm or less than about 200 nm, for example, 5, 10, 15,20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130,140, 150, 160, 170, 180, 190, or 200 nm. In another example, the aqueousliquid dilution composition has a particle size less than 100 nm orabout 100 nm, less than 50 nm or about 50 nm or less than 25 or about 25nm. Typically, the particle size of the aqueous liquid dilutioncomposition is between 5 nm or about 5 nm and 200 nm or about 200 nm, orbetween 5 nm or about 5 nm and 50 nm or about 50 nm.

Typically, the particle size of the provided aqueous liquid dilutioncomposition containing the liquid pre-emulsion composition, whichcontains the non-polar compound, is smaller than the particle size of aliquid containing the non-polar compound (not formulated in a liquidpre-emulsion composition).

iii. Turbidity

In another example, the clarity of the liquid is evaluated and/orexpressed using a turbidity measurement, for example, NephelometricTurbidity Units (NTU), as measured using the provided methods, describedbelow. In this example, turbidity is measured optically, to get valueindicating the cloudiness or haziness of the liquid, which correlateswith particles in suspension in the liquid. The more clear a liquid is,the lower its turbidity value.

In one example, the clear aqueous liquid dilution composition has aturbidity value (NTU) of 30 or about 30; or an NTU value of less than 30or about 30, for example, less than 29 or about 29, less than 28 orabout 28, less than 27 or about 27, less than 26 or about 26, less than25 or about 25, less than 24 or about 24, less than 23 or about 23, lessthan 22 or about 22, less than 21 or about 21, less than 20 or about 20,less than 19 or about 19, less than 18 or about 18, less than 17 orabout 17, less than 16 or about 16, less than 15 or about 15, less than14 or about 14, less than 13 or about 13, less than 12 or about 12, lessthan 11 or about 11, less than 10 or about 10, less than 9 or about 9,less than 8 or about 8, less than 7 or about 7, less than 6 or about 6,less than 5 or about 5, less than 4 or about 4, less than 3 or about 3,less than 2 or about 2, less than 1 or about 1; or 29 or about 29, 28 orabout 28, 27 or about 27, 26 or about 26, 25 or about 25, 24 or about24, 23 or about 23, 22 or about 22, 21 or about 21, 20 or about 20, 19or about 19, 18 or about 18, 17 or about 17, 16 or about 16, 15 or about15, 14 or about 14, 13 or about 13, 12 or about 12, 11 or about 11, 10or about 10, 9 or about 9, 8 or about 8, 7 or about 7, 6 or about 6, 5or about 5, 4 or about 4, 3 or about 3, 2 or about 2, 1 or about 1, or 0or about 0.

In another example, the turbidity value of the aqueous liquid dilutioncomposition is less than 200 or less than about 200, for example, 200,175, 150, 100, 50, 25 or less.

In another example, it is desirable that the aqueous liquid dilutioncomposition contains a turbidity value that is comparable, for example,about the same as, the same as, or less than or greater than, theturbidity value of another liquid, for example, a beverage notcontaining the liquid pre-emulsion composition or an aqueous liquiddilution composition made by the provided methods.

b. Stability

Typically, the provided aqueous liquid dilution compositions containingthe pre-emulsion compositions are stable, for example, free from one ormore changes over a period of time, for example, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11 or 12 months, 1, 2, 3, 4 or more years.

In one example, the compositions are stable because they are free fromoxidation or substantial oxidation over time. In another example, theyare stable because they remain clear over time. In another example, thestable compositions remain safe and/or desirable for human consumptionover time. In one example, stability refers to the lack of precipitatesforming in the compositions over the period of time. In a relatedexample, the compositions are stable because they do not exhibit“ringing,” formation of a whitish or opaque ring around the perimeter ofthe container holding the liquid, typically at the surface of theliquid. Ringing typically is undesirable, particularly in the case of aliquid for human consumption, for example, a beverage.

In another example, the composition is stable if it does not exhibit anyvisible phase separation over a period of time, for example, after 24hours, after one week or after one month. In one example, thecompositions are stable if they exhibit one or more of these describedcharacteristics, over time, when kept at a particular temperature. Inone example, the compositions remain stable at room temperature, forexample, 25° C. or about 25° C. In another example, the compositionsremain stable at between 19° C. and 25° C. In another example, thecompositions remain stable at refrigerated temperatures, for example, 4°C. or about 4° C., or at frozen temperature, for example, at −20° C. orabout −20° C.

Stability refers to a desirable property of the provided compositions,for example, the ability of the provided compositions to remain freefrom one or more changes over a period of time, for example, at least orover 1, 2, 3, 4, 5, 6 or more days, at least or over 1, 2, 3, 4, or moreweeks, at least or over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or moremonths, or at least or over 1, 2, 3, 4 or more years. In one example,the composition is stable if it is formulated such that it remains freefrom oxidation or substantial oxidation over time. In another example,the stable compositions remain clear over time. In another example, thestable compositions remain safe and/or desirable for human consumptionover time. In one example, stability refers to the lack of precipitatesforming in the compositions over the period of time. In a relatedexample, stability refers to the lack of “ringing” over the period oftime. In another example, the composition is stable if it does notexhibit any visible phase separation over a period of time, for example,after 24 hours, after one week or after one month. In one example, thecompositions are stable if they exhibit one or more of these describedcharacteristics, over time, when kept at a particular temperature.

In one example, the compositions are stable when stored at roomtemperature, for example, 25° C. or about 25° C. In another example, thecompositions remain stable when stored at between 19° C. and 25° C. Inanother example, the compositions remain stable when stored atrefrigerated temperatures, for example, 4° C. or about 4° C., or atfrozen temperature, for example, at −20° C. or about −20° C.

c. Desirable Characteristics for Human Consumption

In one example, the liquid dilution composition is desirable for humanconsumption, for example, for use in a food or beverage. Differentproperties of the liquid dilution composition can contribute to itsdesirability as a consumable product. For example, taste, smell,clarity, color, crystal formation, precipitation and “ringing,” all canrelate to desirability.

In one example, the liquid dilution composition has a pleasant tasteand/or smell, for example, due to one or more flavors added to thepre-emulsion composition and/or to the aqueous medium. In anotherexample, the liquid dilution composition containing the pre-emulsioncomposition is free from an unpleasant taste or smell, for example, a“fishy” taste or smell. In one example, the pre-emulsion compositionsmells or tastes less unpleasant, for example, less fishy, compared toanother aqueous liquid dilution composition.

In another example, the aqueous liquid dilution composition is desirablebecause it does not have crystals or has fewer crystals compared withanother aqueous liquid dilution composition. In another example, theaqueous liquid dilution composition is desirable because it does notexhibit ringing.

d. Safety

Typically, the aqueous liquid dilution compositions containing thepre-emulsion compositions are safe for human consumption, for example,containing only ingredients approved by the FDA for human consumption,for example GRAS-certified ingredients. In one example, one or more ofthe ingredients, for example, all the ingredients, are Kosher-certified.Safety of the compositions also relates to stability over time. Lack ofor minimum oxidation of the compositions over time can contribute to thesafety of the compositions.

e. Oral Bioavailability

In one example, the non-polar compounds, for example, the non-polaractive ingredients, contained in the aqueous liquid dilutioncompositions exhibit a high or relatively high bioavailability, forexample, a bioavailability that is higher than a liquid containing thenon-polar active ingredient alone (i.e. not formulated in the liquidpre-emulsion composition). Bioavailability relates to the ability of thebody to absorb the non-polar active ingredient into a particular space,tissue cell and/or cellular compartment. Typically, non-polar activeingredients in liquids having small particle sizes are better absorbedthan those with larger particle sizes.

C. Methods for Making Pre-emulsion Compositions Containing Non-polarCompounds

Also provided are methods for making the pre-emulsion compositions.General equipment and steps of the methods are detailed below. In oneexample, the general methods for making the pre-emulsion compositionsare carried out using a bench-top manufacturing process, which is usedfor making relatively smaller-sized batches of the pre-emulsioncompositions. In another example, the general methods for making thepre-emulsion compositions are carried out using a scaled-upmanufacturing processes, which is used for making relatively largerbatches of the pre-emulsion compositions. The bench-top process can bescaled up to the scaled-up process. Any pre-emulsion composition madeusing the bench-top method can be made using the scaled-up process, byscaling up the method.

1. Equipment for Making the Pre-emulsion Compositions

Various equipment, for example, vessels for mixing, heating, holdingand/or packaging the ingredients, for example, tanks and beakers;scales; mixers, including standard mixers and homogenizers; heating andcooling apparatuses, including water-jacketed tanks, hot plates, waterbaths and chillers (coolers), including recirculating coolers, waterbaths and ice baths; transfer apparatuses, for example, transfer means,for example, pumps, hoses, sanitary fittings; ball valves; purifiers,for example, filters, for example, carbon filters, ion exchangeequipment, reverse osmosis equipment, end-point filters and end productfilters; evaluation means, for example, pH and temperature meters; andother equipment, is used in various steps of the provided methods formaking the pre-emulsion compositions. The choice of equipment depends ona plurality of factors, including batch size and manufacturing process.

a. Scales

One or more scales typically is used to measure the ingredients beforeadding them to the appropriate vessel. Alternatively, the ingredientscan be weighed in the vessel, for example in a tank mounted on top of ascale.

Any of a plurality of well-known, commercially sold scales can be usedto weigh the ingredients. Choice of scale(s) can depend on a number offactors, including the mass of the final pre-emulsion composition beingmade and the ingredient being weighed. In one example, multiple scalesare used to weigh the various ingredients of the pre-emulsioncomposition. In general, relatively larger capacity (weight) scale(s)are used in making larger batches of pre-emulsion composition whilerelatively smaller capacity scale(s) are used in making smaller batches.

Exemplary of the scales used with the provided methods to weigh theingredients are a Toledo Scale (Model GD13x/USA), a Sartorius BasicAnalytical Scale (Model BA110S) which is a basic series analytical scalewith a 110 g capacity and a resolution of 0.1 mg; and an OHAUS Scale(Model CS2000), which is a compact portable digital scale having a 2000g capacity and a resolution of 1 g.

b. Purifiers, Including Filters

Purifiers, typically more than one purifier, for example, filters, areused in the provided methods to remove impurities in the ingredientsprior to their addition to the pre-emulsion composition and/or from thefinal pre-emulsion composition and/or an intermediate phase of thepre-emulsion composition. In one example, one or more purifiers, forexample, carbon filters, ion exchange purifiers, reverse osmosispurifiers, and/or end point filters are used to filter water, forexample, city water, prior to its addition to compositions providedherein, for example, to the dilution compositions, for example, toremove impurities, for example, sediment, from the water.

Exemplary of the purifiers that can be used with the provided methodsare filters, for example, 100 micron filters and carbon filters, whichare filters that use activated carbon to remove impurities by chemicaladsorption. Carbon filtering typically is used for water purificationand are particularly effective at filtering out chlorine, sediment,volatile organic compounds and other impurities. Typically, theparticles removed by carbon filters are between about 0.5 microns andabout 50 microns. Other filters are well known and can be used with theprovided methods.

Also exemplary of the purifiers that can be used in the provided methodsare reverse osmosis purifiers, which use mechanical pressure to purifyliquids, for example, water. In one example, the pressure forces thewater through a semi-permeable membrane to remove impurities.

Also exemplary of the purifiers that can be used in the provided methodsare ion exchange purifiers, for example, an ion exchange purifier usinga resin bed, for example, a zeolite resin bed, to replace salts, e.g.cations, for example, magnesium and calcium, with other cations, forexample, sodium and potassium cations. Such purifiers can be purchased,for example, from Aquapure Filters, Clarkston, Mich.

In another example, an end product filter (e.g. a 100 micron FSI filter,Product Number BPEM 100-5GP). This filter is used to filter anyimpurities out of the final product (e.g. the final pre-emulsioncomposition). Other filters are known and can be used with the providedmethods.

c. Vessels for Mixing the Ingredients

One or more, typically two or more, vessels, for example, tanks, forexample, water-jacketed tanks; flasks; cylinders; pots; and/or beakers,for example, Pyrex® beakers, are used in the provided methods to containthe ingredient(s) of the liquid pre-emulsion compositions, for example,during mixing and/or heating or cooling. Typically, vessels are used formixing and heating the ingredients of the composition. In anotherexample, an additional vessel, for example, a holding and/or packagingtank, is used for holding and/or packaging the pre-emulsion composition.

A number of vessels are available for mixing ingredients. Typically, thevessels are cleaned, for example, rinsed, soaped and/or sanitizedaccording to known procedures, prior to use and between uses.

In one example, typically used with the bench-top process, the vessel isa container, for example, a bench-top container, for example, flasks,beakers, for example, Pyrex® beakers, vials, measuring containers,bottles and/or other bench-top containers.

In another example, typically used with the scaled-up manufacturingprocess, the vessels are tanks, for example, mixing tanks andholding/packaging tanks. Typically, the tanks are equipped with one ormore mixers, for example, a standard mixer and/or homogenizer, which areused to mix the ingredients added to the tank. In one example, the tankfurther is equipped with a heating and/or cooling device. For example,the tank can be a water-jacketed tank. The temperature of thewater-jacketed tank is controlled through the water-jacket, for example,to heat the contents, for example, while mixing.

Exemplary of the tanks that can be used with the provided methods arewater-jacketed tanks, for example, the Overly 550 Gallon water jacketedtank (Model 10576501G), which has a 550 gallon capacity, the Schweitzers450 gallon tank (Model # 5214-C; e.g. sold by Machinery and Equipment,Pomona Calif.), which has a 450 gallon capacity and the Royal 190 gallonwater jacketed tank (Model 9977-5), which has a 190 gallon capacity andwhen mixing smaller volumes. Other tanks are well known and can be usedwith the provided methods for mixing the pre-emulsion compositions, forexample, the phases of the pre-emulsion compositions.

d. Mixers

Mixers are used in the provided methods to blend, mix and/or homogenizethe liquid pre-emulsion compositions and/or various ingredients of theliquid pre-emulsion compositions. In one example, the mixers are used tokeep the ingredients and/or mixture circulating to maintain temperature,viscosity and/or other parameters of the mixture. Exemplary of themixers that can be used in the provided methods are standard mixers, forexample, standard mixers, which can be used, for example, to mix theingredients, to maintain a homogeneous mixture while heating. Exemplaryof the standard mixers is a LIGHTNIN® mixer (LIGHTNIN, Rochester, N.Y.),for example, Model Numbers XJC117 and ND-2. In one example, theLIGHTNIN® mixers are fixed-mount, gear drive high-flow mixers, for usewith closed tanks. Another example of a standard mixer is a mixer soldby IKA®, for example, overhead IKA® mixers, for example, model Nos.RW-14 Basic and RE-16S, which are laboratory stirrers and can be used tomix ingredients. In one example, the mixer(s) are attached to thevessels, for example, the tanks, for example, mounted or clamped ontothe tanks, for example, the top of the tanks. In another example, themixers are placed in the vessels for mixing.

Also exemplary of the mixers used with the provided methods arehomogenizers (also called shears), which typically are used tohomogenize the ingredients after they are combined. The homogenizerstypically provide high shear dispersion of solids and emulsification ofimmiscible liquids at high shear rates. Exemplary of the homogenizersthat can be used in the provided methods are high-shear homogenizers,for example, reverse homogenizers sold by Arde Barinco, Inc., Norwood,NJ, for example, Model CJ-50, which is a 3600 rpm mixer having a 6 inchrotor diameter, a tip speed of 5575 ft/minute and an emersion depth of33 inches; and Model CJ-4E, which is a 10,000 rpm mixer with fan-cooledmotor, optimized for 1 to 5 gallon batch sizes, having a 1.875 inchrotor diameter, a tip speed of 4920 rpm and an immersion depth of 16inches. The homogenizer typically has six separate openings at thebottom and top, which concentrates the liquid into six chambers,reducing the surface volume and creating a shear effect. Otherhomogenizers, for example, other reversible homogenizers sold by ArdeBarinco Inc., can be used with the provided methods.

In one example, the homogenizer is attached to the top of the vessel,for example, the tank, for example, by clamps or by channel locks and anelectrical hoist. In another example, the homogenizer is placed in thevessel. The Arde Barinco reversible homogenizers contain axial flowimpellers, which create two distinct mixing actions, depending ondirection. Downward “vortex flow” pulls solids from top and bottom ofthe mixture, while upward “umbrella flow” controls mixing at the highestshear and recirculation rates without splashing or incorporation of air.The reversible homogenizers typically are equipped with an adjustablebaffle plate, which can be adjusted to control the type of mixing, forexample at different times during homogenization.

A number of additional mixers are well known and can be used with theprovided methods. Exemplary of the mixers that can be used with theprovided methods are shears, inline mixers/mixing, Ribbon, Plow/PaddleBlenders Forberg Mixers, Conveyors, Bag Dumps & Compactors, V-Blenders,Blade Mixers, Double Cone Mixers, Continuous Mixers, Speedflow Mixers,Batch Mixers, Double Ribbon Blenders, Paddle and Ribbon Mixers withChoppers, Plow Blenders/Turbulent Mixers, Fluidizing Forberg-TypeMixers, Air Mixers, Active Mixers, Passive Mixers, Top Entry Mixers,Side Entry Mixers, Static Mixers, Fixed Entry Mixers, PortableMixers—both direct and gear drive, Sanitary Mixers, Drum Mixers, BulkContainer (IBC) Mixers, Lab Stirrers, Variable Speed Mixers, doughmixer, vertical mixer, spiral mixer, twin arm mixer, fork mixer, doublespiral mixer, all agitators, agitator mixers, Banbury Mixers, RubberMixers, Blondheim Mixers, Chum Mixers, Conical Mixers, ContinuousMixers, Disperser Mixers, Pan Mixers, Emulsifier Mixers, Hobart Mixers,Liquifier Mixers, Littleford Mixers, Meat Mixers, Plow Mixers, MixmullerMixers, Nauta Mixers, Oakes Mixers, Planetary Mixers, Pony Mixers, PUGMixers, Ribbon Mixers, Ross Mixers, Rotary Mixers, Sigma Mixers, SingleArm Mixers, Tote Bin Mixers, Tumble Mixers, Vacuum Mixers, TurbolizerMixers, Twin Shell Mixers, V-Type Mixers, Zig-Zag Mixers side armmixers, hand-held mixers, stir rods, stir bars, magnetic mixers andoverhead mixers, for example, mechanical and/or electric overheadmixers.

e. Heating Apparatuses

One or more, typically more than one, heating apparatuses are used inthe provided methods to control the temperature of the ingredients,phases and/or pre-emulsion composition, typically while mixing.

In one example, the heating apparatuses are water-jackets. In thisexample, the vessels used to mix the ingredients are water jacketedtanks. The water jacket can be controlled, for example, using a controlpanel, to adjust the temperature of the contents of the vessel.

Alternatively, other heating apparatuses can be used to heat theingredients, and/or pre-emulsion compositions. Exemplary of heatingapparatuses that can be used with the provided methods are immersibleand/or submersible heaters, for example, 12 KW or 13 KW sanitaryheaters, which are food-grade heaters that are immersed into the tankswhile mixing, typically for applications requiring high heat, forexample, temperatures greater than about 60° C. or 60° C., or greaterthan 80° C. or about 80° C. Also exemplary of heating apparatuses arestoves, for example, propane stoves. Also exemplary of the heatingapparatuses are hot plates, for example, the Thermolyne hot plate, modelnumber 846925 or model number SP46615. Typically, the heater is capableof heating the mixture to between 45° C. or about 45° C. and 85° C. orabout 85° C., for example, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85° C. Typically, theheater is capable of heating the mixture to 60° C. or 60° C., forexample, providing low heat.

f. Cooling Apparatuses

One or more cooling apparatuses can be used with the provided methods,for example, to cool the ingredients during mixing, for example, tochill the mixture while homogenizing. Exemplary of the coolingapparatuses are chillers, for example, recirculating coolers, which canbe attached to the vessel, for example, remotely or by a tank mounted inthe cooler, to recirculate fluid from the tank, through the chiller andback to the tank, in order to rapidly cool and maintain the temperatureof the mixture during mixing. Exemplary of an open-loop chiller that canbe attached to the tank and used with the provided methods are chillerssold by Turmoil, West Swanzey, N.H., for example, open or closed-loopcoolers, for example, model No. OC-1000 RO. Other cooling apparatusesare well known and can be used with the provided methods.

Also exemplary of the cooling apparatuses are water baths and ice baths,for example, water baths and/or ice baths in which the vessel(s) areplaced, for example, during homogenizing.

Typically, the cooling apparatus can be used to cool the liquid tobetween 25° C. or about 25° C. and 45° C. or about 45° C., for example,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44 or 45° C., typically between 25° C. and 43° C., typically between35° C. and 43° C., for example, 26.5° C. Typically, the cooling is rapidcooling, for example, cooling to between 25° C. or about 25° C. and 45°C. or about 45° C., for example, between 35° C. and 43° C., for example,26.5° C., in between 15 minutes or about 15 minutes and 2 hours or about2 hours, typically, between 30 minutes or about 30 minutes and 60minutes or about 60 minutes, for example, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59 or 60 minutes.

g. Transfer Means

Transfer means are used with the provided methods to transfer liquidfrom one vessel to another vessel, for example, to transfer the contentsof one or more vessels to one or more other vessels, for example, totransfer the pre-emulsion composition to a holding vessel (e.g. aholding tank). Exemplary of the equipment used for the transfer meansare transfer pumps and associated accessories, for example, ball valves,sanitary fittings (for example, sanitary fittings sold by Granger, Inc.,Lake Forrest Il) and transfer hoses (for example, hoses sold bySani-Tech West, Oxnard, Calif.), for example, food grade hoses attachedto the transfer pumps. Exemplary of the transfer pumps that can be usedwith the provided methods is the Teel Pump (Model 2P377B), Granger, Inc.Lake Forrest Ii, a self-priming pump having a power rating of 2 HP, 60Hz voltage 208-230/460 AC, speed of 3450 rpm. Other pumps, for example,other self-priming pumps from Grainger, Inc., can be used as part of thetransfer means in the provided methods. Alternatively, transfer meanscan include means for manually transferring the liquid to anothervessel, for example, by pouring, pipetting and/or other well-knownmethods of manually transferring liquids.

h. Evaluation Equipment

Evaluation equipment is used to evaluate one or more properties of thecompositions, for example, the phases of the compositions and/or thefinal pre-emulsion compositions. For example, evaluation equipment canbe used to measure one or more parameters of the pre-emulsioncompositions and/or the phases, for example, the temperature and the pHof the liquids. Exemplary of the evaluation equipment are pH meters andtemperature meters. Exemplary of the pH/temperature meters is the pH andtemperature meter sold by Hanna Instruments, (model number HI 8314),which can be used to measure both the temperature and the pH of themixture(s). Also exemplary of temperature meters are temperature probes,for example, digital and/or water-proof temperature probes, for example,temperature probes sold by Cooper-Atkins, Middlefield, Conn., forexample, the digital waterproof temperature probe (Model # DPP400W) fromCooper-Atkins. Other evaluation equipment for evaluating liquids and/oremulsions is well known and can be used with the provided methods.

2. General Methods for Making the Pre-emulsion Compositions

In general, the provided methods for making the pre-emulsioncompositions include steps for combining (e.g. mixing, heating andhomogenizing) the ingredients of the compositions, typically in one ormore vessels, to form the pre-emulsion compositions, and for packagingthe compositions, e.g. by transfer to a holding/packaging vessel or apackaging or storage container. In some examples, the methods includeadditional steps, such as evaluation, addition of further ingredients,packaging and filtering. The provided methods can be carried out using abench-top manufacturing process (typically for small batch sizes).Alternatively, the methods can be carried out using a scaled-upmanufacturing process (typically for larger batch sizes). Each of theprovided pre-emulsion compositions can be made using either a scaled-upprocess or a bench-top process. In one example, after the pre-emulsioncomposition first is made using the bench-top process, the method isscaled up to make larger quantities of the pre-emulsion compositionusing the scaled-up process. When formulating the pre-emulsioncompositions according to the provided methods, the initial pre-emulsioncomposition typically is made by a bench-top method. In one example ofthe formulation methods, a selected formulation then is made using ascaled-up process. Any of the pre-emulsion compositions provided hereincan be made with the provided methods, using either manufacturingprocess. Any method described herein, where the bench-top method isused, can be scaled-up for production of the pre-emulsion compositionsusing the scaled-up process.

Generally, the provided methods for making the pre-emulsion compositionsinclude a first dissolving step, which typically includes mixing andheating the ingredients of the composition, for example, in a vessel.The provided methods further include a homogenizing step, e.g. mixingwith a homogenizer. Typically, one or more of the dissolving and/orhomogenizing steps (e.g. standard mixer and/or homogenizer) is performedsimultaneously with heating. Alternatively, the steps can be performedsequentially in any order, simultaneously, or partially simultaneously.

Typically, for heating, the ingredients are heated to a low heattemperature, for example, to 60° C. or about 60° C.

Typically, the methods generally include a packaging step, whereby themixed and heated composition is packaged, for example, transferred, e.g.hot filled into a container, e.g. a packaging container. Typically, thecomposition is cooled in the packaging container.

The provided methods can include additional steps, for example,evaluation steps, steps for adding additional ingredients, purification(e.g. filtration) steps, and/or packaging/holding steps, as detailedbelow.

a. Combining the Ingredients i. Weighing the Ingredients

Typically, the ingredients are weighed and/or measured, for example,using one or more scales (e.g. one or more of the scales describedherein), before they are added to the mixing vessel (e.g. any vesseldescribed herein). In one example, the amount of each ingredient to beadded is determined according to the provided methods for formulatingthe pre-emulsion compositions. Typically, the desired concentration, byweight (w/w), of the final pre-emulsion composition is used to calculatethe amount of each ingredient that is added to the vessel.Alternatively, the desired volume per weight, volume per volume orweight per volume can be used to calculate the correct amount of aningredient to be measured and added to the vessel.

ii. Dissolving First Ingredient(s)—Standard Mixer

Typically, a subset of the ingredients, initial ingredients are addedfirst to the mixing vessel. In one example, the initial ingredients areall or most of the ingredients, but not including the non-polarcompound(s). In another example, the ingredients are all or most of theingredients, but not including the surfactant, for example, the TPGSsurfactant. Typically, in order to dissolve the initial ingredients,these first ingredient(s) are mixed in the mixing vessel using astandard mixer (e.g. any of the standard mixers described herein) andheated, typically simultaneously or, in part, simultaneously, using aheating apparatus (e.g. any of the heating apparatuses describedherein). Typically, the ingredients are heated such that the ingredientsreach a low heat temperature, for example, between about 45° C. or about45° C. and 85° C. or about 85° C., for example, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85°C., typically, 60° C. or 60° C. In another example, the initialingredients are heated to a higher temperature, for example, to 80° C.or about 80° C., for example, 82.2° C. In this example, the ingredientsare heated to this higher temperature, typically for an hour, forexample, until dissolved. In this example, the mixture typically isfiltered, for example, using a 100 micron filter, before proceeding tothe next step, e.g. addition of additional ingredients, for example, thesurfactant, and homogenization. Typically, mixing and/or heating ofingredients in the vessel is continued until the ingredientsdissolve—e.g. until they become homogeneous, for example at the heatedtemperature. One or more temperature meters can be used to measure thetemperature during mixing.

iii. Homogenizing the Mixture

Typically, after the initial ingredients are dissolved, additionalingredients are added to the vessel before homogenizing the mixture. Inone example, the additional ingredients added prior to homogenizationare one or more non-polar compound(s), e.g. non-polar activeingredient(s) (and optionally, any other ingredients, for example,emulsion stabilizer). In another example, the one or more additionalingredients added prior to homogenization is one or more surfactants,for example, TPGS. The additional ingredient(s) is added to the vessel,with continued heating and mixing. In this step, the ingredientstypically are homogenized, using a homogenizer (e.g. any of thedescribed homogenizers). Typically, the homogenizing is carried out inthe vessel containing the dissolved initial ingredients (e.g. the samevessel). Alternatively, a different vessel can be used for addition ofthe non-polar active ingredient and homogenization. Typically,homogenization is carried out using a mixer that is capable ofemulsifying liquids (e.g. a high-shear mixer), for example, ahomogenizer, for example, a reversible homogenizer. Typically, theingredients are homogenized while maintaining the heated temperature,for example between about 45° C. or about 45° C. and 85° C. or about 85°C., for example, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84 or 85° C., typically, 60° C. or about 60°C. Typically, the homogenizing is carried out using the mixer (e.g.homogenizer) at low speed, for example, low rpm, for example, between850 or about 850 rpm and 1200 or about 1200 rpm, for example, 850, 900,950, 1000, 1050, 1100, 1150 or 1200 rpm.

The ingredients typically are homogenized, continuously orintermittently, until the ingredients become homogeneous at thetemperature, for example, at between about 45° C. or about 45° C. and85° C. or about 85° C., for example, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85° C., typically,60° C. or about 60° C. In one example, the baffle plate of the mixer isadjusted, for example, by moving the baffle plate further down into themixture or further up out of the mixture, to control the type of mixing,for example, to switch from downward flow to upward flow and vice versa,during mixing of the composition. In another example, the homogenizercan be adjusted to increase or decrease shear or to maintain the shearat a particular speed. Methods for homogenizing ingredients are wellknown and other methods can be used to homogenize in the providedmethods.

iv. Ingredients and Order of Addition

Typically, the ingredients added to the vessel to make the providedpre-emulsion compositions are hydrophobic or amphipathic ingredients. Inone example, there is no aqueous ingredient added to the composition. Inanother example, less than 1% or about 1% or less than 5% or about 5%,by weight, of the composition is represented by aqueous ingredients. Theingredients can be added simultaneously and/or sequentially, in aspecific order. In one example, one or more ingredients (e.g. initialingredients) is added first and heated, prior to addition of furtheringredient(s). For example, the non-polar compound can be mixed andheated with one or more solvent, for example, an oil, for example,flaxseed oil and/or Vitamin E oil, until the non-polar compound isdissolved in the oil, prior to addition of the other ingredients. In oneexample, when the composition includes one or more of a surfactant (e.g.a TPGS surfactant), a preservative, and non-polar active ingredient,these ingredients are added sequentially, in the following order: 1)surfactant(s), 2) preservative(s), 3) 4) non-polar active ingredient(s).In this example, the non-polar active ingredient(s) typically is addedafter the other ingredients have dissolved, prior to homogenization.

In another example, when the composition includes one or more of asurfactant (e.g. a TPGS surfactant), a preservative, and non-polaractive ingredient, these ingredients are added sequentially, in thefollowing order: 1) preservative(s), 2) non-polar active ingredient(s),3) surfactant(s). In this example, the surfactant typically is addedafter the other ingredients have dissolved (and been filtered) prior tohomogenization. In another example, when the composition includes one ormore of a surfactant, a preservative, solvent and non-polar activeingredient, these ingredients are added sequentially, in the followingorder: 1) solvent(s), 2) preservative(s), 3) non-polar activeingredient(s), 4) surfactant(s). In this example, the surfactant(s)typically is added after the other ingredients have dissolved, prior tohomogenization.

In one example, when the composition includes a surfactant, particularlywhen the surfactant is a surfactant that is solid at room temperature,for example, tocopherol polyethylene glycol succinate surfactant, thesurfactant is the first ingredient added to the vessel. In anotherexample, the surfactant, for example, TPGS, is the last ingredient addedto the vessel. Typically, when the ingredients include an emulsionstabilizer, the emulsion stabilizer is the last ingredient added to thevessel. Typically, the non-polar compound either is the last ingredientadded to the vessel, or is added immediately prior to addition of theemulsion stabilizer, which is the last ingredient added to the vessel.In this example, the non-polar active ingredient(s) typically is addedafter the other ingredients have dissolved, prior to homogenization.

b. Additional Steps

Typically, one or more additional steps is carried out, following mixingand heating the ingredients. For example, the composition can beevaluated (e.g. by measuring pH and/or temperature of the pre-emulsioncomposition). In another example, one or more additional ingredients canbe added to the composition. In another example, the pre-emulsioncomposition is transferred to a holding vessel or a packaging vessel,for example, a holding/packaging vessel, for example, aholding/packaging tank. In another example, the nanoemulsion ispurified, for example, filtered, prior to use. In one example, additionof additional ingredients, evaluation and/or purification, can becarried out in the holding/packaging vessel. Other additional steps canbe carried out prior to use.

i. Additional Ingredients

In one example, additional ingredients, for example pH adjusters and/orflavors, can be added to the composition after it is formed. In oneexample, citric acid and/or phosphoric acid is added to adjust the pH,for example, until the pH reaches a pH between 2.5 and 3.5, typically,between 2.6 or about 2.6 and 3.2 or about 3.2, for example, 2.6, 2.7,2.8, 2.9, 3.0, 3.1, or 3.2. In another example, one or more flavors isadded to the pre-emulsion composition, for example, to improve the tasteand/or smell of the pre-emulsion composition and/or beverages containingthe pre-emulsion composition. Other additional ingredients also can beadded to the composition. Typically, the additional ingredients areadded to the vessel containing the composition, for example, the mixingvessel, or another vessel, for example, a holding/packaging vessel.Typically, the composition is mixed (e.g. using any of the describedmixers, typically standard mixers), while the additional ingredients areadded.

ii. Evaluation of the Pre-emulsion Composition

Typically, the pre-emulsion composition is evaluated prior to use.Typically, the pH and/or temperature are measured, for example, using apH and temperature meter. In one example, the pH and/or temperature areevaluated after additional ingredients have been added. In one example,further ingredients can be added to adjust the parameters afterevaluation.

iii. Filtering

Typically, after all the ingredients have been added and madehomogeneous in the composition, the composition is filtered using anend-product filter (e.g. a 100 micron end-product filter), to remove anyimpurities.

iv. Transfer and/or Packaging

In one example, the ingredients, typically the mixture of ingredients(e.g. the pre-emulsion composition) is transferred, using one or moretransfer means, to another vessel, for example, a holding or packagingvessel and or a storage container. Any transfer means can be used. Forexample, any means for transferring the contents of one vessel toanother vessel as described above, for example, transfer pumps andassociated equipment, for example, sanitary fittings, hoses and/or ballvalves; and manual transfer means, for example, pouring and/or pipettingmeans or other known transfer means. In some examples, the mixture iskept clean, for example, sterile during transfer, for example, by usingtransfer means with sanitary fittings and/or combining the phases in asterile environment.

In one example, the mixture is transferred to a holding tank. In anotherexample, the pre-emulsion composition, after being made and filtered, istransferred, e.g. by hot filling while the composition is still aliquid, to a storage container, e.g. a vial, plastic bottle, or schollebag-in-a-box type packaging. Typically, the composition is allowed tocool naturally in the storage container. Alternatively, a coolingapparatus, e.g. a refrigerator, freezer or water bath, can be used tocool the composition in the storage container. Typically, thecomposition solidifies as it cools in the storage container, e.g.becoming a waxy solid.

3. Bench-top Process

In one example of the provided methods for making the pre-emulsioncompositions, the steps of the methods are carried out using a bench-topmanufacturing process, which is carried out on a bench, counter, tableor other surface. Typically, the bench-top process is used to makecompositions having relatively smaller volumes than those made with thescaled-up process, for example, volumes less than 1 L or about 1 L orless than 1 gallon or about 1 gallon, for example, less than about 500mL, for example, 1000, 900, 800, 700, 600, 500, 450, 400, 350, 300, 250,200, 150, 100, 50 or less.

For the bench-top process, the equipment typically is sufficientlycompact to be used on a bench top or other similar surface, typicallysufficiently compact to be moved, for example, lifted, by the artisanusing the methods. For example, the vessels typically are bench-topvessels, for example, flasks, beakers, vials, measuring containers,bottles and/or other bench-top containers. In one example, the vesselsin the bench-top process is a Pyrex® beaker. Typically, the mixers aremixers that can be used in the bench-top vessels, for example, standardmixers, including hand-held mixers, stir rods, stir bars, magneticmixers and overhead mixers, for example, mechanical and/or electricoverhead mixers and/or other mixers that can be used in the vessels.Exemplary of appropriate bench-top mixers are standard mixers, forexample, standard mixers sold by IKA®, for example, overhead IKA®mixers, for example, model Nos. RW-14 Basic and RE-16S, which arelaboratory stirrers and can be used to mix ingredients, e.g. to mix anddissolve the initial ingredients. Also exemplary of appropriatebench-top mixers are homogenizers, for example, reversible homogenizers,including The Arde Barinco reversible homogenizer, Model no. CJ-4E,which can be used to emulsify the phases. Typically, the heatingapparatuses are those that can be used with the bench-top vessels, forexample, hot plates. The cooling apparatuses typically are apparatusessuited for use with the smaller bench-top vessels, for example, icebaths and/or water baths into which the vessels can be placed, forexample, for rapid cooling. The evaluation means used in the bench-topprocess, for example, the temperature and/or pH meters, typically arecapable of being placed in the bench-top vessels.

Generally, for the bench-top process, the dissolving step is carried outby mixing and heating in a bench-top vessel, for example, a flask,beaker, vial, measuring container, bottle and/or other bench-topcontainer. The mixing typically is carried out using an appropriatebench-top mixer, for example, a standard mixer, such as a hand-heldmixer, stir rod, stir bar, magnetic mixer and/or overhead mixer, forexample, the mixer sold by IKA®, for example, overhead IKA® mixers, forexample, model Nos. RW-14 Basic and RE-16S, which are laboratorystirrers. For homogenizing, a reverse homogenizer typically is used.Typically, heating the ingredients during mixing is carried out using aheating apparatus appropriate to the bench-top method, for example, aheating apparatus that one or more of the vessels can be placed upon,for example, a hot plate. Typically, transfer, e.g. transferring thecomposition into a storage container, packaging vessel or holdingvessel, is carried out manually, for example, by pouring, pipettingand/or another manual transfer means.

4. Scaled-up Manufacturing Process

In another example of the provided methods for making the pre-emulsioncompositions, the steps of the methods are carried out using a scaled-upmanufacturing process, which typically is used when making emulsionshaving relatively larger volumes than those made with the bench-topprocess, for example, volumes greater than 1 L or about 1 L or greaterthan 1 gallon or about 1 gallon, for example, greater than about 500 mL,for example, at least 0.5 L, 1 L, 2 L, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450,500, 550, 600, 650, 700, 800, 900, 1000 or more gallons. In general,equipment used for the scaled-up process is compatible with these largervolume batches (batch sizes) of the pre-emulsion compositions. Forexample, the vessels typically are tanks, for example, water jacketedtanks, which are equipped with water jackets that can be used as heatingapparatuses to heat the ingredients, for example, whilemixing/homogenizing the ingredients. The water jackets typically arecontrolled via control panels. Similarly, the transfer means typicallyinclude transfer pumps and associated fittings, for example, ball valvesand hoses. Exemplary of mixers that are used in the scaled-up processare standard mixers (for example, mounted mixers, for example LIGHTNINGmixers, for example, Model XJC117 (a fixed-mount, gear drive high-flowmixer, and Model ND2. An exemplary scaled-up process is set forth inFIG. 1 and described in this section, below. The provided methods formaking the pre-emulsion compositions can be performed using thisexemplary scaled-up process, or any variation of the scaled-up process,for example, eliminating one or more steps of the exemplary process,adding one or more steps according to the provided method, and/orsubstituting steps and/or equipment according to the methods providedherein.

FIG. 1 sets forth a an exemplary scaled-up process 100 for making theliquid pre-emulsion composition. This exemplary scaled-up processincludes the following steps:

a. Combining the Ingredients i. Dissolving the InitialIngredients—Standard Mixing

After the initial ingredients (e.g. one or more ingredients typicallynot including the non-polar active ingredient) are weighed/measured,they are added to the mixing vessel. In this example of the scaled upprocess, set forth in FIG. 1, the vessel is a mixing tank 101.Typically, in the scaled-up method, the mixing tank is a water-jacketedtank. The initial ingredient(s) are mixed using a standard mixer 104,for example, a LIGHTNIN® mixer (for example, model no. XJC117, afixed-mount gear drive high-flow mixer), attached to the tank, forexample, mounted on the top of the tank. In this example, the heatingapparatus, for heating the ingredients during mixing, is the waterjacket of the water-jacketed tank; temperature on the water-jacket iscontrolled via a control pane. The ingredients are mixed and heated,typically to low heat (e.g. 60° C.), until dissolved, according to theprovided methods.

ii. Addition of the Non-polar Compound and Homogenizing

In this example, set forth in FIG. 1, once the initial ingredients aredissolved (by heating and mixing with the standard mixer) additionalingredient(s), for example, the non-polar compound (e.g. non-polaractive ingredient) is added, and the mixture is homogenized. In theexample set forth in FIG. 1, to begin the homogenization step, ahomogenizer 105 (e.g. an Arde Barinco, Inc. reversible homogenizer),mounted on the mixing tank, is turned on, for example, at 850-1200 rpm.The additional ingredient(s) (e.g. the non-polar active ingredient) isadded and the mixture homogenized, typically while continuing to heatthe mixture, e.g. while maintaining low heat. The mixture is homogenizedby continued mixing with the homogenizer 105. The homogenizer can beadjusted, for example, by adjusting the baffle plate on the homogenizerto achieve and maintain an emulsion, for example, by moving the baffleplate further into the forming emulsion and/or further out of theforming mixture. The homogenization is continued, with heating, untilthe ingredients dissolve.

b. Additional Steps

After the homogenization step, one or more additional steps typicallyare carried out. In one example, the ingredients are transferred, viatransfer means 102, which include a transfer pump (e.g. a Teel pump,model 2P377B, sold by Granger, Inc.), sanitary fittings, transferhose(s) (e.g. food grade hoses sold by Sani-Tech West) and ballvalve(s), to a packaging or holding tank 103. The packaging/holding tankcan be used to add additional ingredients, to evaluate the composition,or to hold the composition. Typically, the pre-emulsion composition isfiltered using an end-product filter 106, which is, for example, a 100micron end-product filter. In the example shown in FIG. 1, thecomposition can be filtered directly from the mixing tank, or it can befiltered after transfer to the packaging/holding tank. The compositionfinally is transferred, for example, using transfer means 102, to astorage container 107. Typically, the composition is transferred intothe storage container while it is still at a heated temperature, forexample, between 48° C. or about 48° C. and 60° C. or about 60° C. Inthis example, the composition then solidifies (developing a waxyconsistency) while in the storage container.

Variations of this exemplary scaled-up process (FIG. 1) also can becarried out using the provided methods, to make the pre-emulsioncompositions. For example, by elimination and/or modification of one ormore steps and/or equipment, according to the general methods providedherein.

D. Methods for Making the Liquid Dilution Compositions Containing theDiluted Pre-Emulsion Compositions

Also provided herein are methods for diluting the pre-emulsioncompositions to make liquid dilution compositions, typically, aqueousliquid dilution compositions, containing the non-polar compounds.Generally, the pre-emulsion composition is diluted into an aqueousmedium, for example, a beverage, for example, soda, water milk, coffee,tea, juice, fitness drinks, nutritional beverage, nutritionalsupplement, or other aqueous food or beverage. The pre-emulsioncomposition and the aqueous medium can be mixed, for example, bystirring and/or blending or by any known mixing means. The pre-emulsioncomposition disperses into the aqueous medium to form an aqueous liquiddilution composition, for example, a clear or partially clear aqueousliquid dilution composition. The aqueous liquid dilution composition canbe evaluated, for example, to assess the clarity, taste, smell, and/orstability of the liquid.

In one example, the pre-emulsion composition is diluted in the aqueousmedium, for example, water by heating the aqueous medium, for example,by heating the aqueous medium, for example, to at least 40° C. or atleast about 40° C., for example, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50or more ° C., for example, 48.9° C. (120° F. or about 120° F.). In thisexample, the pre-emulsion composition is added, at an appropriatedilution, as described herein, to the heated aqueous medium, and stirreduntil dispersed or dissolved in the solution. In one example, thepre-emulsion composition is heated before addition to the aqueousmedium, for example, to at least 40° C. or at least about 40° C., forexample, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more ° C., forexample, 48.9° C. (120° F. or about 120° F.). In another example, thepre-emulsion composition is added to the medium without heating.

The resulting liquid dilution composition can then be cooled, forexample, to room temperature, for example, 25° C. or about 25° C.Following dilution, the aqueous liquid dilution composition can bepackaged, for example, by transferring to containers, for example, vialsor beverage containers. In one example, a portion of the liquid dilutioncomposition is transferred to vials for analysis, for example,evaluation of properties, such as clarity, turbidity, taste, smell,ringing, crystal formation and/or other properties.

Exemplary of equipment used for diluting the pre-emulsion compositionsto form the liquid dilution compositions containing the dilutedpre-emulsion compositions are beakers, for example, Pyrex® glassbeakers, hot plates, for example, the Thermolyne hot plate, model number846925 or model number SP46615, stir rods, temperature meters, forexample, temperature probes, for example, Cooper Temperature Probes(model no. DPP400W) and scales, for example, the OHUAS 2.0 Kg scale(Model # CS2000) and/or the Sartorius Analytical Scale (model BA110S).

1. Dilutions

Typically, the provided pre-emulsion compositions can be diluted intoaqueous media to form aqueous liquid dilution compositions over a widerange of dilutions. In one example, the pre-emulsion composition can bediluted so that the aqueous liquid dilution composition contains between0.05 g or about 0.05 g and 10 g or about 10 g, typically between 0.05 gand 5 g, of the liquid pre-emulsion composition per 8 fluid ounces ofthe liquid, at least 8 fluid ounces of the liquid or less than 8 fluidounces of the liquid, or per single serving of the liquid. For example,the pre-emulsion composition can be diluted so that the aqueous liquiddilution composition contains 0.05 g, 0.06 g, 0.07 g, 0.08 g, 0.09 g,0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 2 g,3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, or 10 g of the pre-emulsioncomposition per 8 fluid ounces, about 8 fluid ounces, or at least 8fluid ounces or at least about 8 fluid ounces of the aqueous medium, forexample 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35,40, 45, 50, 100, 200 or more fluid ounces, of aqueous medium.

In another example, the pre-emulsion composition is diluted so that theaqueous liquid dilution composition contains between 1 mL or about 1 mLand 10 mL or about 10 mL of the liquid pre-emulsion composition, forexample, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL or 10 mLof the pre-emulsion composition, per 8 fluid ounces, about 8 fluidounces, at least 8 fluid ounces or at least about 8 fluid ounces, orless than 8 fluid ounces or less than about 8 fluid ounces, or perserving size, of the aqueous medium, for example 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 100, 200 or morefluid ounces, of aqueous medium.

In another example, the liquid pre-emulsion composition is diluted sothat the aqueous liquid dilution composition contains at least 10 mg orabout 10 mg, typically at least 25 mg or about 25 mg, typically at least35 mg, of the non-polar compound, for example, the non-polar activeingredient, per 8 fluid ounces (0.236588 liters) or about 8 fluidounces, at least 8 fluid ounces (0.236588 liters) or at least about 8fluid ounces of the aqueous medium, or less than 8 ounces or less thanabout 8 ounces (0.236588 liters), or per serving size, of the aqueousmedium; for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 25, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180,190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350,375, 400, 425, 450, 475, 500, 550, 600, 700, 800, 900, 1000, 1500, 2000mg, or more, of the non-polar compound per at least 8 fluid ounces or atleast about 8 fluid ounces (0.236588 liters) of aqueous medium.

2. Analyzing the Aqueous Liquid Dilution Compositions Containing theLiquid Pre-emulsion Compositions

Properties of the aqueous liquid dilution compositions containing theliquid pre-emulsion compositions can be evaluated using a number ofdifferent evaluation means. For example, the clarity; desirability forhuman consumption, for example, pleasant taste, and/or smell, forexample, lack of “fishy” taste/smell, lack of “ringing” and lack ofcrystal formation; stability, for example, lack of oxidation, “ringing,”precipitation and/or visible phase separation, over time; and safety forhuman consumption, can be evaluated. Several of these properties can beevaluated empirically, for example, by observing the liquids immediatelyor over time, or by smelling and/or tasting the liquids. In one example,after evaluation of the aqueous liquid dilution compositions, thepre-emulsion compositions are re-formulated to adjust one or moreparameters. In another example, the dilution factor can be adjusted.

a. Clarity/Turbidity

Clarity of the aqueous liquid dilution compositions can be evaluatedusing one or more of several approaches, or example, empiricalobservation, measurement of particle size and/or measurement of aturbidity value. The measurement can be qualitative or quantitative. Inone example, a particular quantitative or qualitative clarity value isspecified. In another example, the clarity of a liquid can be expressedin relation to the clarity of another liquid, for example, an aqueousliquid dilution composition made according to the provided methods, or abeverage, for example, a beverage that does not contain the liquidpre-emulsion composition. In this example, the liquid can be as clearas, less clear, or more clear than the other liquid. For example, anaqueous liquid dilution composition containing the liquid pre-emulsioncomposition diluted in a beverage can be as clear or about as clear asthe same beverage that does not contain the pre-emulsion composition.Either type of evaluation can be done qualitatively, for example, byempirical evaluation, or quantitatively, for example, by taking ameasurement of particle size or turbidity.

i. Empirical Evaluation

In one example, the clarity/turbidity of the aqueous liquid dilutioncomposition is evaluated qualitatively, for example, by observation. Inone example, a liquid is considered clear if it does not have a cloudyappearance and/or if it contains no particles or few particles that areobservable with the naked eye. In another example, the liquid can beconsidered relatively clear or relatively turbid based on comparison toother liquids, for example, water, fruit juice, soda, and/or milk and/orother aqueous liquid dilution composition(s) made according to theprovided methods. For example, the aqueous liquid dilution compositioncan be as clear or about as clear as water or another liquid, forexample, a beverage. For example, the liquid containing the liquidpre-emulsion composition diluted in a beverage can be as clear or aboutas clear as the beverage that does not contain the liquid pre-emulsioncomposition. In a related example, the liquid can be clear or partiallyclear when there is no substantial difference, for example, noobservable difference, between the aqueous liquid dilution compositioncontaining the pre-emulsion composition and the aqueous medium that doesnot contain the pre-emulsion composition. A clear liquid is notnecessarily colorless. For example, a yellow liquid that contains no (orfew) visible particles or cloudiness can be clear. In another example,the lack of crystal formation or of “ringing” can be indicative of aclear liquid.

ii. Particle size

In another example, clarity/turbidity are assessed by quantitativelymeasuring particle size and/or number of particles, in the aqueousliquid dilution composition. In this example, the clarity can beexpressed as a numerical representation of the particle size, or as acomparison to the particle size of another liquid.

Methods for measuring particle size of liquids are well known. Anymethod for measuring particle size can be used, provided that it issensitive to the particle size in the expected and/or appropriate rangesof the provided aqueous liquid dilution compositions. For example,particle size analysis is available commercially, for example, fromDelta Analytical Instruments, Inc., North Huntingdon, Pa. In oneexample, the particle size of the aqueous liquid dilution composition ismeasured, for example, by Delta Analytical Instruments, Inc., using alight-scattering analyzer, for example, a dynamic light scatteringanalyzer, for example, the Horiba® LB-550, which can measure particlesizes within a range of 0.001 micron to 6 micron and uses aFourier-Transform/Iterative Deconvolution technique for reporting dataand can measure sample concentrations from ppm to 40% solids; theHoriba® LA-920, which is a laser light-scattering instrument having anHe—Ne laser and a tungsten lamp that can determine particle sizes from0.02 micron to 2000 micron using Mie Theory; and other analyzersavailable from Delta Analytical Instruments, Inc.

Alternatively, particle size can be measured by viewing the liquid undera microscope under magnification, for example, a 640× magnification.Particle size then can be measured by comparison to a measuringstandard, for example, a ruler, which also is viewed under themagnification. In one example, particles about 25 nm or greater thanabout 25 nm are visible, while particles less than 25 nm are notvisible, for example under a 640× magnification.

iii. Turbidity Measurement

In another example, the clarity/turbidity of the liquid is evaluatedand/or expressed using a turbidity measurement, for example,Nephelometric Turbidity Units (NTU). In this example, turbidity ismeasured optically, to obtain a value indicating the cloudiness orhaziness of the liquid, which correlates with the number and size ofparticles suspended in the liquid. The more clear a liquid is, the lowerits turbidity value. Turbidity can be measured optically, for example,using a nephelometer, an instrument with a light and a detector. Thenephelometer measures turbidity by detecting scattered light resultingfrom exposure of the aqueous liquid dilution composition to an incidentlight. The amount of scattered light correlates with the amount and sizeof particulate matter in liquid, and thus, the clarity. For example, abeam of light will pass through a sample having low turbidity withlittle disturbance, creating very little scattered light, resulting in alow turbidity (NTU) value reading. Other methods for measuring turbiditycan be used, including commercial services for measuring turbidity, forexample, the services available through ACZ Laboratories, Inc.,Steamboat Springs, Colo.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

E. EXAMPLES Example 1 General Procedure Used to Make the Pre-emulsionCompositions of Examples 2-7

Tables 2A(i)-7F below, set forth ingredients that were included in aplurality of different pre-emulsion compositions, described in Examples2A through 7F. The pre-emulsion compositions were made according to theprovided methods. Each of the pre-emulsion compositions contained one ormore non-polar active ingredients.

The non-polar active ingredient(s) used in each pre-emulsion compositionis/are described in each individual Example. The surfactant used in eachpre-emulsion composition was a tocopherol polyethylene glycol succinatesurfactant (the TPGS surfactant sold under the name Vitamin E TPGS® byEastman Chemical Company). The preservative used in each pre-emulsioncomposition was a natural (GRAS-certified) preservative, benzyl alcohol.

In some of the Examples (where indicated), a solvent was used as aningredient in the pre-emulsion composition. In these Examples, thesolvent was Vitamin E oil, sold by ADM Natural Health and Nutrition,Decatur, Ill., under the name Novatol™ 5-67 Vitamin E(D-alpha-Tocopherol; ADM product code 410217). This oil contained atleast 67.2% Tocopherol and approximately 32.8% soybean oil. Pre-emulsioncompositions similar to the pre-emulsion compositions set forth in theseexamples alternatively could be made using an alternative or additionalsolvent(s), for example, a Flaxseed oil solvent, for example, theflaxseed oil from Sanmark LLC, Greensboro, N.C. (Sanmark Limited,Dalian, Liaoning Province, China), which contains not less than (NLT)50% C18:3 alpha-linolenic acid.

Each of Tables 2A(i)-7F sets forth, for each pre-emulsion composition,the total milligrams (mg) per serving and the mg of each ingredient perserving (serving size is indicated), the percentage, by weight (of thetotal pre-emulsion composition), for each ingredient, the amount (g) ofeach ingredient that was added to make a batch of the indicated batchsize (g).

Each of the pre-emulsion compositions set forth in Examples 2A-7F wasmade using a bench-top process according to the provided methods. Eachof the pre-emulsion compositions could be made alternatively by scalingup the bench-top process, to make the pre-emulsion compositions using ascaled-up manufacturing process of the provided methods, for example, tomake larger batch sizes of the pre-emulsion compositions in thefollowing Examples. Accordingly, each of the pre-emulsion compositionsin Examples 2A-7F also can be made with the provided methods, using thescaled-up process.

The bench-top process for making the pre-emulsion compositions inExamples 2A-7F was carried out using the following general steps.Further details for each pre-emulsion composition are provided in eachindividual example.

For each of the pre-emulsion compositions set forth in Examples 2A-7Fbelow, the indicated amount of each ingredient was weighed using aToledo Scale (Model GD13x/USA), Sartorius Basic Analytical Scale (ModelBA110S) or an OHAUS Scale (Model CS2000). Selection of scale wasdependent on the weight of each ingredient being weighed.

The initial ingredients (all ingredients except the non-polar activeingredient(s)) then were added, in the indicated amounts (g/batch), to avessel (a Pyrex® beaker), and mixed using a standard mixer (IKA® modelNo. RE-16 1 S, which is an overhead mixer (laboratory stirrer)compatible with the bench-top process). While mixing, the ingredientswere heated using a heating apparatus, which was a hot plate (aThermolyne hot Plate Model #SP46615), to reach a temperature of 60° C.

Once these initial ingredients had dissolved, e.g. formed a homogeneousmixture, and reached the desired temperature, e.g. 60° C., the non-polaractive ingredient(s) was/were added. The ingredients then werehomogenized by placing a reversible homogenizer (Arde Barinco, Inc.;Model CJ-4E) in the vessel (beaker) and turning it on at 850-1200 RPM.Mixing with the homogenizer was continued while maintaining thetemperature using the hot plate. The baffle plate on the homogenizer wasadjusted to achieve and maintain an emulsion, for example, by moving thebaffle plate further into and/or out of the ingredient mixture. Themixture was homogenized until it became homogeneous at 60° C.

Unless otherwise indicated, when the ingredients included a surfactant,a preservative and one or more non-polar active ingredients, theseingredients were added sequentially, in the following order: 1)surfactant; 2) preservative; 3) non-polar active ingredient(s). When theingredients included a surfactant, a preservative, a solvent and one ormore non-polar active ingredient(s), these ingredients were addedsequentially, in the following order: 1) surfactant; 2) preservative; 3)solvent(s); 4) non-polar active ingredient(s). The ingredients wereheated with the hot plate until the temperature reached 60° C. Atemperature meter (temperature probe (Model #DPP400W, Cooper-Atkins))was used to evaluate (measure) the temperature of the mixingingredients.

The composition then was filtered, using a 100 micron end-product filterand then packaged (transferred) by filling into one or more storagecontainers, for example, plastic bottles or 5 gallon pails, where it wascooled to room temperature (about 25° C.). Alternatively, the mixturecould be packaged into a bag-in-a-box type storage container. Themixture became a solid at room-temperature, having a waxy consistency.Thus, each of the pre-emulsion compositions in Examples 2-7 was asemi-solid or solid at room temperature, having a waxy consistency, andbecame liquid upon heating, for example, to 60° C.

Example 2 Pre-emulsion Compositions Having DHA-Containing Non-PolarCompounds

Examples 2A-B set forth the details of pre-emulsion compositionscontaining non-polar compounds containing the omega-3 polyunsaturatedfatty acid, DHA. These pre-emulsion compositions were made using thegeneral procedure outlined in Example 1, above.

Example 2A Pre-emulsion Compositions Having Fish Oil Non-Polar Compounds

Tables 2A(i)-(vi) set forth the ingredients that were included in aplurality of pre-emulsion compositions having non-polar activeingredients containing fish oil, which contain different amounts of theomega-3 polyunsaturated fatty acids, DHA and EPA. These pre-emulsioncompositions were made using the general procedure outlined in Example1, above. Each of the pre-emulsion compositions set forth in Tables2A(i)-(vi) used one of two different fish oil non-polar activeingredients. The first fish oil-containing non-polar active ingredient(used in the pre-emulsion compositions set forth in Tables 2A(i)-(ii))was Denomega™ 100, fish oil, which contained about 13% DHA and about 13%EPA. The second fish oil-containing non-polar active ingredient (used inthe pre-emulsion compositions set forth in Tables 2A(iii)-(vi)) wasOmega-3 Fish Oil EE, made by O3C Nutraceuticals, supplied by JedwardsInternational Inc., Quincy, Mass., which contained about 70% (74%) DHAand about 10% (9.3%) EPA.

TABLE 2A(i) Pre-emulsion composition having 10% of a Fish Oil-ContainingNon-Polar Active Ingredient and 89.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch Denomega ™ 100Fish Oil 50 10 15 (13% EPA, 13% DHA) (Non-Polar Active Ingredient)Tocopherol Polyethylene 447.5 89.5 134.25 Glycol Succinate (surfactant)Benzyl alcohol (preservative) 2.5 0.5 .75 Totals 500.000 100.0000 150

TABLE 2A(ii) Pre-emulsion composition having 30% of a FishOil-Containing Non-Polar Active Ingredient and 69.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch Denomega ™ 100 Fish Oil 150 30 45 (13% EPA, 13% DHA) (Non-PolarActive Ingredient) Tocopherol Polyethylene 347.5 69.5 104.25 GlycolSuccinate (surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75 Totals500.000 100.0000 150

TABLE 2A(iii) Pre-emulsion composition having 10% of a FishOil-Containing Non-Polar Active Ingredient and 89.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch : 50 10 15 Omega-3 Fish Oil EE, (10% EPA, 70% DHA) (Non-PolarActive Ingredient) Tocopherol Polyethylene 447.5 89.5 134.25 GlycolSuccinate (surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75 Totals500.000 100.0000 150

TABLE 2A(iv) Pre-emulsion composition having 20% of a FishOil-Containing Non-Polar Active Ingredient and 79.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch : 100 20 20 Omega-3 Fish Oil EE, (10% EPA, 70% DHA) (Non-PolarActive Ingredient) Tocopherol Polyethylene 397.5 79.5 79.5 GlycolSuccinate (surfactant) Benzyl alcohol (preservative) 2.5 0.5 .5 Totals500.000 100.0000 100

TABLE 2A(v) Pre-emulsion composition having 30% of a Fish Oil-ContainingNon-Polar Active Ingredient and 69.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch Omega-3 FishOil EE, 150 30 45 (10% EPA, 70% DHA) (Non-Polar Active Ingredient)Tocopherol Polyethylene 347.5 69.5 104.25 Glycol Succinate (surfactant)Benzyl alcohol (preservative) 2.5 0.5 .75 Totals 500.000 100.0000 150

TABLE 2A(vi) Pre-emulsion composition having 10% of a FishOil-Containing Non-Polar Active Ingredient, 79.5% TPGS and 10% Vitamin EOil Solvent mg/ Percent (by weight) 0.5 mL of pre-emulsion Ingredientserving composition g/batch Omega-3 Fish Oil EE, 50 10 15 (10% EPA, 70%DHA) (Non-Polar Active Ingredient) Tocopherol Polyethylene 397.5 79.5119.25 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.50.5 .75 Vitamin E Oil 5-67 (Solvent) 50 10 15 Totals 500.000 100.0000150

Example 2B Pre-emulsion Compositions Having Algae Oil Non-PolarCompounds

Tables 2B(i)-(iv) set forth the ingredients that were included inpre-emulsion compositions containing an algae oil non-polar activeingredient. This algae oil non-polar active ingredient contained 35% ofthe omega-3 polyunsaturated fatty acid, DHA. These pre-emulsioncompositions were made using the general procedure outlined in Example1, above.

TABLE 2B(i) Pre-emulsion composition having 10% of an AlgaeOil-Containing Non-Polar Active Ingredient, 79.5% TPGS and 10% Vitamin EOil Solvent mg/ Percent (by weight) 0.5 mL of pre-emulsion Ingredientserving composition g/batch Algae Oil (35% DHA) 50 10 15 TocopherolPolyethylene 397.5 79.5 119.25 Glycol Succinate (surfactant) Benzylalcohol (preservative) 2.5 0.5 .75 Vitamin E Oil 5-67 (Solvent) 50 10 15Totals 500.000 100.0000 150

TABLE 2B(ii) Pre-emulsion composition having 20% of an AlgaeOil-Containing Non-Polar Active Ingredient and 79.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch Algae Oil (35% DHA) 100 20 20 Tocopherol Polyethylene 397.5 79.579.5 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.5 0.5.5 Totals 500.000 100.0000 100

TABLE 2B(iii) Pre-emulsion composition having 20% of an AlgaeOil-Containing Non-Polar Active Ingredient and 79.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch Algae Oil (35% DHA) 100 20 56 Tocopherol Polyethylene 397.5 79.5222.6 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.50.5 1.4 Totals 500.000 100.0000 280

TABLE 2B(iv) Pre-emulsion composition having 30% of an AlgaeOil-Containing Non-Polar Active Ingredient and 69.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch Algae Oil (35% DHA) 150 30 84 Tocopherol Polyethylene 347.5 69.5194.6 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.50.5 1.4 Totals 500.000 100.0000 280

Example 3 Pre-emulsion Compositions Having ALA Containing Non-PolarCompounds (Flaxseed Oil)

Tables 3A-3D set forth the ingredients that were included inpre-emulsion compositions containing a flaxseed oil non-polar activeingredient. The flaxseed oil non-polar active ingredient, obtained fromSanmark LLC, Greensboro, N.C. (Sanmark Limited, Dalian, LiaoningProvince, China), contained not less than (NLT) 50% C18:3alpha-linolenic acid. These pre-emulsion compositions were made usingthe general procedure outlined in Example 1, above.

TABLE 3A Pre-emulsion composition having 10% of a FlaxseedOil-Containing Non-Polar Active Ingredient and 89.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch Flaxseed Oil (NLT 50% C18:3 50 10 15 alpha linolenic acid)(Non-Polar Active Ingredient) Tocopherol Polyethylene 447.5 89.5 134.25Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75Totals 500.000 100.0000 150

TABLE 3B Pre-emulsion composition having 20% of a FlaxseedOil-Containing Non-Polar Active Ingredient and 79.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch Flaxseed Oil (NLT 50% C18:3 100 20 30 alpha linolenic acid)(Non-Polar Active Ingredient) Tocopherol Polyethylene 397.5 79.5 119.25Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75Totals 500.000 100.0000 150

TABLE 3C Pre-emulsion composition having 30% of a FlaxseedOil-Containing Non-Polar Active Ingredient and 69.5% TPGS mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch Flaxseed Oil (NLT 50% C18:3 150 30 45 alpha linolenic acid)(Non-Polar Active Ingredient) Tocopherol Polyethylene 347.5 69.5 104.25Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75Totals 500.000 100.0000 150

TABLE 3D Pre-emulsion composition having 10% of a FlaxseedOil-Containing Non-Polar Active Ingredient, 79.5% TPGS and 10% Vitamin EOil Solvent mg/ Percent (by weight) 0.5 mL of pre-emulsion Ingredientserving composition g/batch Flaxseed Oil (NLT 50% C18:3 50 10 15 alphalinolenic acid) (Non-Polar Active Ingredient) Tocopherol Polyethylene397.5 79.5 119.25 Glycol Succinate (surfactant) Benzyl alcohol(preservative) 2.5 0.5 .75 Vitamin E Oil 5-67 (Solvent) 50 10 15 Totals500.000 100.0000 150

Example 4 Pre-emulsion Compositions Having Omega-6 Polyunsaturated FattyAcid Containing Non-Polar Compounds (GLA Borage-Oil)

Tables 4A-4D set forth the ingredients that were included inpre-emulsion compositions containing a non-polar active ingredientcontaining an omega-6 fatty acid. The non-polar active ingredient was aborage oil compound, obtained from Sanmark LLC, Greensboro, N.C.(Sanmark Limited, Dalian, Liaoning Province, China), which was derivedby pressing and isolating oil from the seeds of Borago officinalis L.This oil contained not less than (NLT) 22% C18:3 gamma-linolenic acid(GLA). These pre-emulsion compositions were made using the generalprocedure outlined in Example 1, above.

TABLE 4A Pre-emulsion composition having 10% of a Borage Oil-ContainingNon-Polar Active Ingredient and 89.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch Borage Oil(NLT 22% C18:3 50 10 15 gamma-linolenic acid (GLA)) (Non-Polar ActiveIngredient) Tocopherol Polyethylene 447.5 89.5 134.25 Glycol Succinate(surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75 Totals 500.000100.0000 150

TABLE 4B Pre-emulsion composition having 20% of a Borage Oil-ContainingNon-Polar Active Ingredient and 79.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch Borage Oil(NLT 22% C18:3 100 20 30 gamma-linolenic acid (GLA)) (Non-Polar ActiveIngredient) Tocopherol Polyethylene 397.5 79.5 119.25 Glycol Succinate(surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75 Totals 500.000100.0000 150

TABLE 4C Pre-emulsion composition having 30% of a Borage Oil -ContainingNon-Polar Active Ingredient and 69.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch Borage Oil(NLT 22% C18:3 150 30 45 gamma-linolenic acid (GLA)) (Non-Polar ActiveIngredient) Tocopherol Polyethylene 347.5 69.5 104.25 Glycol Succinate(surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75 Totals 500.000100.0000 150

TABLE 4D Pre-emulsion composition having 10% of a Borage Oil -ContainingNon-Polar Active Ingredient, 79.5% TPGS and 10% Vitamin E Oil Solventmg/ Percent (by weight) 0.5 mL of pre-emulsion Ingredient servingcomposition g/batch Borage Oil (NLT 22% C18:3 50 10 15 gamma-linolenicacid (GLA)) (Non-Polar Active Ingredient) Tocopherol Polyethylene 397.579.5 119.25 Glycol Succinate (surfactant) Benzyl alcohol (preservative)2.5 0.5 .75 Vitamin E Oil 5-67 (Solvent) 50 10 15 Totals 500.000100.0000 150

Example 5 Pre-emulsion Compositions Having Saw Palmetto ExtractNon-Polar Compounds

Tables 5A-5D set forth the ingredients that were included inpre-emulsion compositions containing a non-polar active ingredientcontaining saw palmetto extract. The non-polar active ingredient was theSaw Palmetto, Lipophilic Extract, commercially available from NaturalMedicinals, Inc., Felda, Fla., which contained between about 85% and 90%total fatty acids, including 0.8% Caproic acid, 2% Caprylic acid, 2.4%Capric acid, 27.1 Lauric acid, 10.3 Myristic acid, 8.1% Palmitic acid,0.2% Palmitoleic acid, 2% Stearic acid, 26.7 Oleic acid, 4.9% Linoleicacid, 0.7% linolenic acid, 0.42%; 0.42% phytosterols, including 0.42%beta Sitosterol, 0.09% Campesterol, 0.03% Stigmasterol; and 0.2%moisture. These pre-emulsion compositions were made using the generalprocedure outlined in Example 1, above.

TABLE 5A Pre-emulsion composition having 10% of a Saw PalmettoExtract-Containing Non-Polar Active Ingredient and 89.5% TPGS mg/Percent (by weight) 0.5 mL of pre-emulsion Ingredient servingcomposition g/batch Saw Palmetto Extract 50 10 15 (Non-Polar ActiveIngredient) Tocopherol Polyethylene 447.5 89.5 134.25 Glycol Succinate(surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75 Totals 500.000100.0000 150

TABLE 5B Pre-emulsion composition having 20% of a Saw PalmettoExtract-Containing Non-Polar Active Ingredient and 79.5% TPGS mg/Percent (by weight) 0.5 mL of pre-emulsion Ingredient servingcomposition g/batch Saw Palmetto Extract 100 20 30 (Non-Polar ActiveIngredient) Tocopherol Polyethylene 397.5 79.5 119.25 Glycol Succinate(surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75 Totals 500.000100.0000 150

TABLE 5C Pre-emulsion composition having 30% of a Saw Palmetto Extract-Containing Non-Polar Active Ingredient and 69.5% TPGS mg/ Percent (byweight) 0.5 mL of pre-emulsion Ingredient serving composition g/batchSaw Palmetto Extract 150 30 45 (Non-Polar Active Ingredient) TocopherolPolyethylene 347.5 69.5 104.25 Glycol Succinate (surfactant) Benzylalcohol (preservative) 2.5 0.5 .75 Totals 500.000 100.0000 150

TABLE 5D Pre-emulsion composition having 10% of a Saw PalmettoExtract-Containing Non-Polar Active Ingredient, 79.5% TPGS and 10%Vitamin E Oil Solvent mg/ Percent (by weight) 0.5 mL of pre-emulsionIngredient serving composition g/batch Saw Palmetto Extract 50 10 15(Non-Polar Active Ingredient) Tocopherol Polyethylene 397.5 79.5 119.25Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75Vitamin E Oil 5-67 (Solvent) 50 10 15 Totals 500.000 100.0000 150

Example 6 Pre-emulsion Compositions Having CLA Containing Non-PolarCompounds

Tables 6A-6D set forth the ingredients that were included inpre-emulsion compositions containing a non-polar active ingredientcontaining conjugated linolenic acid (CLA). The non-polar activeingredient was a conjugated linolenic acid (CLA) compound, obtained fromSanmark, LTD (Dalian, Liaoning Province, China; product code 01057-A80),containing 70% CLA. These pre-emulsion compositions were made asdescribed in Example 1, above.

TABLE 6A Pre-emulsion composition having 10% of a CLA-ContainingNon-Polar Active Ingredient and 89.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch CLA (70%) 5010 15 (Non-Polar Active Ingredient) Tocopherol Polyethylene 447.5 89.5134.25 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.50.5 .75 Totals 500.000 100.0000 150

TABLE 6B Pre-emulsion composition having 20% of a CLA-ContainingNon-Polar Active Ingredient and 79.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch CLA (70%) 10020 30 (Non-Polar Active Ingredient) Tocopherol Polyethylene 397.5 79.5119.25 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.50.5 .75 Totals 500.000 100.0000 150

TABLE 6C Pre-emulsion composition having 30% of a CLA -ContainingNon-Polar Active Ingredient and 69.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch CLA (70%) 15030 45 (Non-Polar Active Ingredient) Tocopherol Polyethylene 347.5 69.5104.25 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.50.5 .75 Totals 500.000 100.0000 150

TABLE 6D Pre-emulsion composition having 10% of a CLA-ContainingNon-Polar Active Ingredient, 79.5% TPGS and 10% Vitamin E Oil Solventmg/ Percent (by weight) 0.5 mL of pre-emulsion Ingredient servingcomposition g/batch CLA (70%) 50 10 15 (Non-Polar Active Ingredient)Tocopherol Polyethylene 397.5 79.5 119.25 Glycol Succinate (surfactant)Benzyl alcohol (preservative) 2.5 0.5 .75 Vitamin E Oil 5-67 (Solvent)50 10 15 Totals 500.000 100.0000 150

Example 7 Pre-emulsion Compositions Having Coenzyme Q ContainingNon-Polar Compounds (CoQ10)

Tables 7A-7F set forth the ingredients that were included inpre-emulsion compositions containing a non-polar active ingredientcontaining Coenzyme Q10. The non-polar active ingredient was a CoenzymeQ 10 (CoQ10) compound, sold under the name Kaneka Q10™ (USPUbidicarenone) by Kaneka Nutrients, L.P., Pasadena, Tex., which containsgreater than 98% ubidicarenone (ubiquinone). These pre-emulsioncompositions were made as described in Example 1, above.

TABLE 7A Pre-emulsion composition having 30% of a CoQ10-ContainingNon-Polar Active Ingredient and 69.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch CoQ10(ubidicarenone) 150 30 900 (Non-Polar Active Ingredient) TocopherolPolyethylene 347.5 69.5 2085 Glycol Succinate (surfactant) Benzylalcohol (preservative) 2.5 0.5 15 Totals 500.000 100.0000 3000

TABLE 7B Pre-emulsion composition having 10% of a CoQ10-ContainingNon-Polar Active Ingredient, 79.5% TPGS and 10% Vitamin E Oil Solventmg/ Percent (by weight) 0.5 mL of pre-emulsion Ingredient servingcomposition g/batch CoQ10 (ubidicarenone) 50 10 15 (Non-Polar ActiveIngredient) Tocopherol Polyethylene 397.5 79.5 119.25 Glycol Succinate(surfactant) Benzyl alcohol (preservative) 2.5 0.5 .75 Vitamin E Oil5-67 (Solvent) 50 10 15 Totals 500.000 100.0000 150

TABLE 7C Pre-emulsion composition having 12.5% of a CoQ10-ContainingNon-Polar Active Ingredient and 87% TPGS mg/ Percent (by weight) 0.8 mLof pre-emulsion Ingredient serving composition g/batch CoQ10(ubidicarenone) 100 12.5 264 (Non-Polar Active Ingredient) TocopherolPolyethylene 696 87.0 1837.44 Glycol Succinate (surfactant) Benzylalcohol (preservative) 4 0.5 10.56 Totals 800.000 100.0000 2112

TABLE 7D Pre-emulsion composition having 16.7% of a CoQ10-ContainingNon-Polar Active Ingredient and 82.8% TPGS mg/ Percent (by weight) 0.6mL of pre-emulsion Ingredient serving composition g/batch CoQ10(ubidicarenone) 100 16.7 264.53 (Non-Polar Active Ingredient) TocopherolPolyethylene 497 82.8 1311.55 Glycol Succinate (surfactant) Benzylalcohol (preservative) 3 0.5 7.92 Totals 600.000 100.0000 1584

TABLE 7E Pre-emulsion composition having 22% of a CoQ10-ContainingNon-Polar Active Ingredient and 77.5% TPGS mg/ Percent (by weight) 0.5mL of pre-emulsion Ingredient serving composition g/batch CoQ10(ubidicarenone) 110 22.0 55 (Non-Polar Active Ingredient) TocopherolPolyethylene 387.5 77.5 193.75 Glycol Succinate (surfactant) Benzylalcohol (preservative) 2.5 0.5 1.25 Totals 500.000 100.0000 250

TABLE 7F Pre-emulsion composition having 31.5% of a CoQ10-ContainingNon-Polar Active Ingredient and 68% TPGS mg/ Percent (by weight) 0.5 mLof pre-emulsion Ingredient serving composition g/batch CoQ10(ubidicarenone) 157.5 31.5 157.5 (Non-Polar Active Ingredient)Tocopherol Polyethylene 340 68.0 340 Glycol Succinate (surfactant)Benzyl alcohol (preservative) 2.5 0.5 2.5 Totals 500.000 100.0000 500

Example 8 Pre-emulsion Compositions Having Phytosterol ContainingNon-Polar Compounds

Tables 8A through 8G, below, set forth ingredients that were used tomake pre-emulsion compositions with phytosterol-containing non-polaractive ingredients.

Each of the pre-emulsion compositions set forth in Tables 8A-G containeda Phytosterols non-polar active ingredient. This non-polar activeingredient was a Phytosterols compound sold under the name CardioAid™,distributed by B&D Nutrition and manufactured by ADM Natural Health andNutrition, Decatur, Ill., which contained Kosher, Pareve, and Halalplant sterols containing a minimum of 95% plant sterols.

As indicated in individual Tables, certain pre-emulsion compositionscontained one or more additional non-polar active ingredient (e.g. CLA,Safflower Oil and/or saw palmetto extract).

The safflower oil additional non-polar active ingredient, and/orsolvent, was a high linoleic safflower oil distributed by Jedwards,International, Inc., Quincy, Mass., which contained between 5% and 10%(specifically 6.65%) C:16 Palmitic acid, between 1% and 3% (specifically2.81%) C:18 Stearic acid, between 12% and 18% (specifically 14.65%) 18:1Oleic acid, between 70% and 80% (specifically 74.08%) C18:2 Linoleicacid and less than 1% (specifically 0.10%) C18:3 Linolenic acid.

The CLA additional non-polar active ingredient was a conjugatedlinolenic acid (CLA) compound, obtained from Sanmark, LTD (Dalian,Liaoning Province, China; product code 01057-A80), containing 80% CLA.

The saw palmetto extract additional non-polar active ingredient was sawPalmetto, Lipophilic Extract, commercially available from NaturalMedicinals, Inc., Felda, Fla., which contained between about 85% and 90%total fatty acids, including 0.8% Caproic acid, 2% Caprylic acid, 2.4%Capric acid, 27.1 Lauric acid, 10.3 Myristic acid, 8.1% Palmitic acid,0.2% Palmitoleic acid, 2% Stearic acid, 26.7 Oleic acid, 4.9% Linoleicacid, 0.7% linolenic acid, 0.42%; 0.42% phytosterols, including 0.42%beta Sitosterol, 0.09% Campesterol, 0.03% Stigmasterol; and 0.2%moisture.

Other pre-emulsion compositions, similar to the pre-emulsioncompositions set forth in Tables 8A-8G below, could be made by includingone or more other additional non-polar active ingredients, for example,CoQ10, fish oil, algae oil, borage oil, and/or another non-polarcompound, for example, any of the non-polar compounds described herein.

As indicated in individual tables, certain pre-emulsion compositions setforth in Tables 8A-G contained one or more solvents. Exemplary of thesolvents used is Vitamin E oil, sold by ADM Natural Health andNutrition, Decatur, Ill., under the name Novatol™ 5-67 Vitamin E(D-alpha-Tocopherol; ADM product code 410217). This oil contained atleast 67.2% Tocopherol and approximately 32.8% soybean oil. Alsoexemplary of the solvents used was a Flaxseed oil, obtained from SanmarkLLC, Greensboro, N.C. (Sanmark Limited, Dalian, Liaoning Province,China), which contains not less than (NLT) 50% C18:3 alpha-linolenicacid.

The surfactant used in each pre-emulsion composition in Tables 8A-G wasa tocopherol polyethylene glycol succinate (TPGS) surfactant (the TPGSsurfactant sold under the name Vitamin E TPGS® by Eastman ChemicalCompany). The preservative used in each pre-emulsion composition was anatural (GRAS-certified) preservative, benzyl alcohol.

Each of Tables 8A-G sets forth the total milligrams (mg) per serving andthe mg of each ingredient per serving, the percentage by weight (of thetotal pre-emulsion composition), for each ingredient and the amount (g)of each ingredient that was added to make a batch of the indicated batchsize (g).

Each of the pre-emulsion compositions set forth in Tables 8A-G was madeusing a bench-top process according to the provided methods. Each of thepre-emulsion compositions could be made alternatively by scaling up thebench-top process, to make the pre-emulsion compositions using ascaled-up manufacturing process of the provided methods, for example, tomake larger batch sizes of the pre-emulsion compositions in thefollowing Examples. Accordingly, each of the pre-emulsion compositionsin Examples 8A-G also can be made with the provided methods, using thescaled-up process. The bench-top process for making the pre-emulsioncompositions in Tables 8A-G was carried out using the following generalsteps.

For each of the pre-emulsion compositions, the indicated amount of eachingredient was weighed using a Toledo Scale (Model GD13x/USA), SartoriusBasic Analytical Scale (Model BA110S) or an OHAUS Scale (Model CS2000).Which scale was used depended on the weight of the particularingredient.

The following initial ingredients, where indicated, were added,sequentially in the following order, to a vessel (a Pyrex® beaker): 1)any solvent(s) and additional non-polar active ingredient(s), in anyorder; 2) preservative, 3) phytosterols-containing non-polar activeingredient. These ingredients then were mixed, using a standard mixer(IKA® model No. RE-16 1S, which is an overhead mixer (laboratorystirrer) compatible with the bench-top process). While mixing, theingredients were heated using a heating apparatus, a hot plate (aThermolyne hot Plate Model #SP46615), until the temperature reachedabout 82.2° C. and the ingredients had dissolved (about 1 hour).

After the initial ingredients had dissolved, the mixture was filtered,without cooling, through a 100 micron filter. The surfactant (TPGS) thenwas added to the mixture and the mixture was homogenized by placing areversible homogenizer (Arde Barinco, Inc.; Model CJ-4E) in the vesseland turning it on at 850-1200 RPM. Mixing with the homogenizer wascontinued while maintaining a temperature of between about 60° C. andabout 82.2° C., using the hot plate. The baffle plate on the homogenizerwas adjusted to achieve and maintain an emulsion, for example, by movingthe baffle plate further into and/or out of the ingredient mixture.Homogenization was continued until the surfactant dissolved. Atemperature probe (Model #DPP400W, Cooper-Atkins) was used forevaluation, as a temperature meter to measure the temperature of theingredients. After all ingredients had dissolved, the mixture wasfiltered (before cooling) through a 100 micron filter. The filteredmixture was added to a vessel (a Pyrex® beaker). The surfactant then wasadded to the mixture.

The composition then was filtered, using a 100 micron end-product filterand then packaged (transferred) by filling into one or more storagecontainers, for example, plastic bottles or 5 gallon pails, where it wascooled to room temperature (about 25° C.). Alternatively, the mixturecould be packaged into a bag-in-a-box type storage container. Themixture became a solid at room-temperature, having a waxy consistency.Thus, each of the pre-emulsion compositions in Examples 2-7 was asemi-solid or solid at room temperature, having a waxy consistency, andbecame liquid upon heating, for example, to 60° C.

TABLE 8A Pre-emulsion composition with 10% of a Phytosterols Non-PolarActive Ingredient, 79.5% TPGS and 10% Vitamin E Oil Solvent mg/ Percent(by weight) 0.5 mL of pre-emulsion Ingredient serving compositiong/batch Phytosterols (NLT 95%) 50 10 15 (Non-Polar Active Ingredient)Tocopherol Polyethylene 397.5 79.5 119.25 Glycol Succinate (surfactant)Benzyl alcohol (preservative) 2.5 0.5 .75 Vitamin E Oil 5-67 (Solvent)50 10 15 Totals 500.000 100.0000 150

TABLE 8B Pre-emulsion composition with 10.5% of a Phytosterols Non-PolarActive Ingredient, 54% TPGS, 30% Flaxseed Oil Solvent, and 5% SawPalmetto Extract mg/ Percent (by weight) 1 mL of pre-emulsion Ingredientserving composition g/batch Phytosterols (NLT 95%) 105 10.5 10.5(Non-Polar Active Ingredient) Tocopherol Polyethylene 540 54 54 GlycolSuccinate (surfactant) Benzyl alcohol (preservative) 5 0.5 0.5 FlaxseedOil (Solvent) 300 30 30 Saw Palmetto Extract 50 5 5 (AdditionalNon-Polar Active Ingredient) Totals 500.000 100.0000 100

TABLE 8C Pre-emulsion composition with 10.5% of a Phytosterols Non-PolarActive Ingredient, 49.5% TPGS, and 45% Flaxseed Oil Solvent mg/ Percent(by weight) 1 mL of pre-emulsion Ingredient serving composition g/batchPhytosterols (NLT 95%) 50 5 5 (Non-Polar Active Ingredient) TocopherolPolyethylene 495 49.5 49.5 Glycol Succinate (surfactant) Benzyl alcohol(preservative) 5 0.5 0.5 Flaxseed Oil (Solvent) 450 45 45 Totals 500.000100.0000 100

TABLE 8D Pre-emulsion composition with 5% of a Phytosterols Non-PolarActive Ingredient, 45% CLA-containing Non-Polar Active Ingredient, and49.5% TPGS mg/ Percent (by weight) 1 mL of pre-emulsion Ingredientserving composition g/batch Phytosterols (NLT 95%) 50 5 5 (Non-PolarActive Ingredient) Tocopherol Polyethylene 495 49.5 49.5 GlycolSuccinate (surfactant) Benzyl alcohol (preservative) 5 0.5 0.5 CLA (NLT80%) 450 45 45 (Additional Non-Polar Active Ingredient) Totals 500.000100.0000 100

TABLE 8E Pre-emulsion composition with 10% of a phytosterols non-polaractive ingredient, 40% CLA-containing Non-Polar Active Ingredient, and49.5% TPGS mg/ Percent (by weight) 1 mL of pre-emulsion Ingredientserving composition g/batch Phytosterols (NLT 95%) 100 10 10 (Non-PolarActive Ingredient) Tocopherol Polyethylene 495 49.5 49.5 GlycolSuccinate (surfactant) Benzyl alcohol (preservative) 5 0.5 0.5 CLA (NLT80%) 400 40 40 (Additional Non-Polar Active Ingredient) Totals 500.000100.0000 100

TABLE 8F Pre-emulsion composition with 10.5% of a phytosterols non-polaractive ingredient, 40% CLA-containing Non-Polar Active Ingredient, 1%saw palmetto extract and 54% TPGS mg/ Percent (by weight) 1 mL ofpre-emulsion Ingredient serving composition g/batch Phytosterols (NLT95%) 105 10.5 10.5 (Non-Polar Active Ingredient) Tocopherol Polyethylene540 54 54 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 50.5 0.5 CLA (NLT 80%) 340 34 34 (Additional Non-Polar Active Ingredient)Saw Palmetto Extract 10 1 1 (Additional Non-Polar Active Ingredient)Totals 500.000 100.0000 100

TABLE 8G Pre-emulsion composition with 10.5% of a phytosterols non-polaractive ingredient, , 1% saw palmetto extract, 34% safflower oil and 54%TPGS mg/ Percent (by weight) 1 mL of pre-emulsion Ingredient servingcomposition g/batch Phytosterols (NLT 95%) 105 10.5 10.5 (Non-PolarActive Ingredient) Tocopherol Polyethylene 540 54 54 Glycol Succinate(surfactant) Benzyl alcohol (preservative) 5 0.5 0.5 Safflower Oil 34034 34 (Additional Non-Polar Active Ingredient) Saw Palmetto Extract 10 11 (Additional Non-Polar Active Ingredient) Totals 500.000 100.0000 100

Example 9 Dilution of the Pre-emulsion Compositions and Evaluation ofthe Liquid Dilution Compositions

For evaluation of various properties, selected pre-emulsion compositionsdescribed in the Examples above, were diluted, according to the providedmethods, in aqueous medium to form aqueous liquid dilution compositions.The results are described in detail in the Examples below.

Example 9A Dilution and Evaluation of Clarity of the DilutionCompositions: Turbidity Analysis

The DHA-containing pre-emulsion composition made in Example 2B(iii) andthe CoQ10-containing pre-emulsion composition made in Example 7 eachwere diluted in aqueous medium, according to the provided methods fordiluting the pre-emulsion compositions. The resulting aqueous liquiddilution compositions then were evaluated for clarity by measuringturbidity using a nephelometer. Dilution parameters and results of theevaluation are set forth in Table 9A below. For each sample listed inTable 9A, the Example in which the pre-emulsion composition was made isindicated.

Each of the pre-emulsion compositions listed in Table 9A was diluted byadding the amount of pre-emulsion composition indicated in Table 9A tothe amount of water (purified according to the provided methods)indicated in Table 9A. Approximate dilution factors also are listed. Thepre-emulsion compositions were diluted in aqueous medium according tothe provided methods for diluting the pre-emulsion compositions, usingthe following steps:

The indicated amount of water was heated in a Pyrex® beaker, which wasplaced on a Thermolyne hot plate (Model #846925), until the waterreached 49.8° C. The indicated amount of the pre-emulsion composition(about 1 g) then was added to the heated water, and stirred with a stirrod until dispersed. Alternatively, the dilution can be carried out byheating the pre-emulsion composition prior to addition to the water. Theresulting aqueous liquid dilution composition containing the non-polaractive ingredient was cooled to room temperature (about 25° C.). Thecooled liquid dilution composition was added to an Alcon amber-glassscrew-top vial, for evaluation. The DHA-containing liquid dilutioncomposition made from the pre-emulsion composition of Example 2B(iii)included 17.5 mg of DHA in 1000 g (1 L) water.

The vials containing the liquid dilution compositions were sent to ACZLaboratories, Inc., Steamboat Springs, Colo., for turbidity analysisusing a nephelometer. Results are listed in the form of NephelometricTurbidity Units (NTU) and are indicated in Table 9A below. As shown inTable 9A, each of the liquid aqueous compositions containing the dilutedpre-emulsion compositions had an NTU value of less than 300, forexample, less than about 200.

TABLE 9A Turbidity (NTU) of liquid aqueous compositions containing thepre-emulsion compositions Pre- Pre-emulsion Non-Polar emulsioncomposition Active composition Water Approx. of: Ingredient (grams)(grams) Dilution NTU Example DHA- 1.0524 1000 1:1000 165 2B (iii)containing (Algae Oil) Example 7A CoQ10- 0.1661 250 1:1500 208Containing

Example 9B Dilution and Evaluation of Clarity of the DilutionCompositions: Particle Size

The CoQ10-containing pre-emulsion composition of Example 7A, above wassent to Delta Analytical Instruments, Inc for measurement of averageparticle size, which was carried out using the Horiba® LB-550light-scattering analyzer. For this process, the pre-emulsioncomposition from Example 7 was diluted, according to the providedmethods, in aqueous medium to form an aqueous liquid dilutioncomposition. To dilute the compositions for this analysis, the samplewas mixed well and heated in a water bath at 50° C. Then, a few drops ofthe sample was added to 25 mL of water, which also had been heated to50° C. This sample then was cooled to room temperature (25° C.). and putinto a cell, which was used to measure average particle size on theHoribag LB-550 light-scattering analyzer. The clarity of the liquiddilution composition then was evaluated by measuring average particlesize. Results included measurement of the average particle size in thedilution composition, which was measured three times, in separate runs.The measurement for each run and the average of the three runs, areindicated in Table 9B, below. As indicated in Table 9B, the particlesize of the liquid dilution composition was less than 150 nm.

TABLE 9B Particle size of Liquid dilution composition containingcoenzyme Q10 pre-emulsion composition Average Particle Size (nm) Run 1129.7 Run 2 120.2 Run 3 123.5 Average 124.5

Example 10 Free Flowing Powders Having Coenzyme Q Containing Non-PolarCompounds (CoQ10)

The pre-emulsion concentrates of Tables 7C-7F were spray dried to formfree flowing powders containing a non-polar active ingredient containingCoenzyme Q10 according to the general steps described below.

Each of the free flowing powders contained one or more excipients,selected from maltodextrin and gum acacia. The excipients were dissolvedin water while heating to a temperature of 60° C. in a stainless steeltank with a 25 horsepower mixer. The ratio of water to excipients was 2to 1. The maltodextrin was GRAS certified Maltrin® maltodextrins, madeby Grain Processing Corporation, Muscatine, Iowa, which containedmixtures of glucose polymers and had a dextrose equivalence (DE) of lessthan 20. After the excipients were dissolved, the pre-emulsionconcentrates were heated to a temperature of 60° C. and homogenized withthe dissolved excipients using a piston driven homogenizer.

The final mixture containing the pre-emulsion composition encapsulatedin the excipients was spray dried using a cyclone type spray dryer.During this process, the encapsulated pre-emulsion composition wastransferred to the spray drier using a diastolic pump and water wasslowly evaporated while heating and with pressure Each of the resultantproducts was a free flowing powder containing coenzyme Q10 with aparticle size of less than 1 micron. The resultant free flowing powdershave the same NTU as the pre-emulsion concentrates of Tables 7C-7F. Theamount and % by weight of the components of the powders are set forth inTables 10A-10D.

TABLE 10A Free Flowing Powder having 5% of a CoQ10-Containing Non-PolarActive Ingredient and 34.8% TPGS mg/ Percent (by weight) 2 mL of freeflowing Ingredient serving powder g/batch CoQ10 (ubidicarenone) 100 5264 (Non-Polar Active Ingredient) Tocopherol Polyethylene 697.5 34.8751841.4 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.50.125 6.6 35% Maltodextrin and 65% 1200 60 3168.0 Gum Acacia(excipients) Totals 2000.000 100.0000 5280.0

TABLE 10B Free Flowing Powder having 5% of a CoQ10-Containing Non-PolarActive Ingredient and 24.8% TPGS mg/ Percent (by weight) 2 mL of freeflowing Ingredient serving powder g/batch CoQ10 (ubidicarenone) 100 5264 (Non-Polar Active Ingredient) Tocopherol Polyethylene 497.5 24.8751313.4 Glycol Succinate (surfactant) Benzyl alcohol (preservative) 2.50.125 6.6 35% Maltodextrin and 65% 1400 70 3696 Gum Acacia (excipients)Totals 2000.000 100.0000 5280

TABLE 10C Free Flowing Powder having 5.5% of a CoQ10-ContainingNon-Polar Active Ingredient and 19.3% TPGS mg/ Percent (by weight) 2 mLof free flowing Ingredient serving powder g/batch CoQ10 (ubidicarenone)110 5.5 55 (Non-Polar Active Ingredient) Tocopherol Polyethylene 387.519.375 193.75 Glycol Succinate (surfactant) Benzyl alcohol(preservative) 2.5 0.125 1.25 35% Maltodextrin and 65% 1500 75 750 GumAcacia (excipients) Totals 2000.000 100.0000 1000

TABLE 10D Free Flowing Powder having 7.875% of a CoQ10-ContainingNon-Polar Active Ingredient and 17% TPGS mg/ Percent (by weight) 2 mL offree flowing Ingredient serving powder g/batch CoQ10 (ubidicarenone)157.5 7.875 157.5 (Non-Polar Active Ingredient) Tocopherol Polyethylene340 17 340 Glycol Succinate (surfactant) Benzyl alcohol (preservative)2.5 0.125 2.5 35% Maltodextrin and 65% 1500 75 1500 Gum Acacia(excipients) Totals 2000.000 100.0000 2000

Since modifications will be apparent to those of skill in this art, itis intended that this invention be limited only by the scope of theappended claims.

The invention claimed is:
 1. A non-aqueous pre-emulsion composition,consisting essentially of: a polyethylene glycol (PEG)-derivative ofVitamin E in an amount between 65% and 95%, by weight, of thepre-emulsion composition; a non-polar ingredient selected from among anyone or more polyunsaturated fatty acids in an amount between 5% and 35%,by weight, of the pre-emulsion composition; and one or more additionalingredients selected from among co-surfactants in an amount up to 1%, byweight, of the composition, emulsion stabilizers in an amount up to 1%,by weight, of the composition, preservatives in an amount up to 1%, byweight, of the composition, flavors in an amount up to 1%, by weight, ofthe composition, pH adjusters in an amount up to 1%, by weight, of thecomposition, and non-polar solvents that dissolve the non-polar activeingredient and differ therefrom in an amount up to 10%, by weight, ofthe composition, wherein: the pre-emulsion composition has a waxyconsistency, whereby it is a solid or semi-solid at room temperature;not more than 1%, by weight, of the composition, comprises hydrophilicingredients(s), and the composition is a non-aqueous composition; thenon-polar ingredient(s) is/are the active ingredient in the composition;and all the ingredients, including the non-polar ingredient, thePEG-derivative of Vitamin E, and the additional ingredients are 100%, byweight, of the composition.
 2. A method for making a non-aqueouspre-emulsion composition, wherein the composition comprises: apolyethylene glycol (PEG)-derivative of Vitamin E in an amount between65% and 95%, by weight, of the pre-emulsion composition; and one or morenon-polar ingredients selected from among any one or more ofpolyunsaturated fatty acids, coenzyme Q10 compounds and phytosterols inan amount between 5% and 35%, by weight, of the pre-emulsioncomposition, wherein not more than 1%, by weight, of the resultingcomposition, comprises hydrophilic ingredients(s); the method,comprising: (a) mixing and heating the PEG-derivative of Vitamin E; andany ingredients other than the non-polar ingredient; and then (b) addingthe one or more non-polar ingredients to the heated mixture of (a); (c)homogenizing the ingredients; (d) cooling the homogenized ingredients,whereby the homogenized ingredients become waxy in consistency andcontain no more than 1% hydrophilic ingredients, thereby generating thenon-aqueous pre-emulsion composition.
 3. A method for making anon-aqueous pre-emulsion composition, wherein the composition comprises:a polyethylene glycol (PEG)-derivative of Vitamin E in an amount between65% and 95%, by weight, of the pre-emulsion composition; one or morenon-polar ingredients selected from among any one or more ofpolyunsaturated fatty acids, coenzyme Q10 compounds and phytosterols inan amount between 5% and 35%, by weight, of the pre-emulsioncomposition, wherein not more than 1%, by weight, of the resultingcomposition, comprises hydrophilic ingredients(s); and a preservativethat contains benzyl alcohol; the method, comprising: (a) mixing andheating the PEG-derivative of Vitamin E with ingredients other than thenon-polar ingredient; and then (b) adding the one or more non-polaringredients to the heated mixture of (a); (c) homogenizing theingredients; and (d) cooling the homogenized ingredients, whereby thehomogenized ingredients become waxy in consistency and contain no morethan 1% hydrophilic ingredients, thereby generating the non-aqueouspre-emulsion composition.
 4. A method for making a non-aqueouspre-emulsion composition, wherein the composition comprises: apolyethylene glycol (PEG)-derivative of Vitamin E in an amount between65% and 95%, by weight, of the pre-emulsion composition; and one or morenon-polar ingredients in an amount between 5% and 35%, by weight, of thepre-emulsion composition, wherein not more than 1%, by weight, of theresulting composition, comprises hydrophilic ingredients(s), wherein thenon-polar active ingredients contain at least one polyunsaturated fattyacid selected from among omega-3 fatty acids, omega-6 fatty acids andconjugated fatty acids; the method, comprising: (a) mixing and heatingthe PEG-derivative of Vitamin E and ingredients other than the non-polaringredient; and then (b) adding the one or more non-polar ingredients tothe heated mixture of (a); (c) homogenizing the ingredients; (d) coolingthe homogenized ingredients, whereby the homogenized ingredients becomewaxy in consistency and contain no more than 1% hydrophilic ingredients,thereby generating the non-aqueous pre-emulsion composition.
 5. Anon-aqueous pre-emulsion composition, consisting essentially of: apolyethylene glycol (PEG)-derivative of Vitamin E in an amount between79% and 90%, by weight, of the pre-emulsion composition; and a non-polaringredient other than the PEG-derivative of Vitamin E selected fromamong any one or more of polyunsaturated fatty acids, coenzyme Q10compounds and phytosterols in an amount between 10% and 20%, by weight,of the pre-emulsion composition; and one or more additional ingredientsselected from co-surfactants in an amount up to 1%, by weight, of thecomposition, emulsion stabilizers in an amount up to 1%, by weight, ofthe composition, preservatives in an amount up to 1%, by weight, of thecomposition, flavors in an amount up to 1%, by weight, of thecomposition, pH adjusters in an amount up to 1%, by weight, of thecomposition, and non-polar solvents that dissolve the non-polar activeingredient and differ therefrom in an amount up to 10%, by weight, ofthe composition, wherein: the pre-emulsion composition is a solid orsemi-solid at room temperature; not more than 1%, by weight, of thecomposition, comprises hydrophilic ingredients(s); the non-polaringredients) is/are the active ingredient in the composition; and allthe ingredients, including the non-polar ingredient, the PEG-derivativeof Vitamin E, and the optional additional ingredients comprise 100%, byweight, of the composition.
 6. A non-aqueous pre-emulsion composition,consisting essentially of: a polyethylene glycol (PEG)-derivative ofVitamin E in an amount between 65% and 95%, by weight, of thepre-emulsion composition; and, as the active ingredient in thecomposition, one or more non-polar compounds selected from among any oneor more polyunsaturated fatty acids in an amount between 5% and 35%, byweight, of the pre-emulsion composition.
 7. A non-aqueous pre-emulsioncomposition, consisting essentially of: a polyethylene glycol(PEG)-derivative of Vitamin E in an amount between 79% and 90%, byweight, of the pre-emulsion composition; and, as the active ingredientin the composition, one or more non-polar compounds selected from amongone or more polyunsaturated fatty acids, coenzyme Q10 compounds andphytosterols in an amount between 10% and 20%, by weight, of thepre-emulsion composition.
 8. The pre-emulsion composition of claim 1,wherein the polyethylene glycol (PEG)-derivative of Vitamin E is atocopherol polyethylene glycol diester (TPGD).
 9. The pre-emulsioncomposition of claim 8, wherein the TPGD is selected from amongtocopherol polyethylene glycol succinate (TPGS), tocopherol sebacatepolyethylene glycol, tocopherol dodecanodioate polyethylene glycol,tocopherol suberate polyethylene glycol, tocopherol azelaatepolyethylene glycol, tocopherol citraconate polyethylene glycol,tocopherol methylcitraconate polyethylene glycol, tocopherol itaconatepolyethylene glycol, tocopherol maleate polyethylene glycol, tocopherolglutarate polyethylene glycol, tocopherol glutaconate polyethyleneglycol, and tocopherol phthalate polyethylene glycol, or a TPGS analog.10. The pre-emulsion composition of claim 9, wherein the TPGS isTPGS-1000 or D-α TPGS.
 11. The pre-emulsion composition of claim 1,wherein the PEG-derivative of Vitamin E contains a PEG moiety selectedfrom among any one or more of methylated PEG (m-PEG), PEG-OH, PEG-NHS,PEG-aldehyde, PEG-SH, PEG-NH₂, PEG-CO₂H, and branched PEGs.
 12. Thepre-emulsion composition of claim 1, the PEG-derivative of Vitamin Econtains a PEG moiety having a molecular weight of between about 200Daltons to about 20,000 Daltons.
 13. The pre-emulsion composition ofclaim 1 that contains a preservative in an amount sufficient to preservethe composition.
 14. The pre-emulsion composition of claim 13, whereinthe preservative contains benzyl alcohol.
 15. The pre-emulsioncomposition of claim 1 that contains a solvent that dissolves thenon-polar active ingredient and differs therefrom, wherein the amount ofsolvent is sufficient to dissolve the non-polar active ingredient. 16.The pre-emulsion composition of claim 15, wherein the solvent contains aVitamin E oil, a flaxseed oil or a combination thereof.
 17. Thepre-emulsion composition of claim 1 that contains-an emulsionstabilizer, at an amount sufficient to stabilize the composition. 18.The pre-emulsion composition of claim 1 that contains a co-surfactant,at an amount sufficient to stabilize the composition.
 19. Thepre-emulsion composition of claim 18, wherein the co-surfactant containsa phospholipid.
 20. The pre-emulsion composition of claim 19, whereinthe co-surfactant contains phosphatidylcholine.
 21. The pre-emulsioncomposition of claim 1, wherein the non-polar active ingredient containsat least one polyunsaturated fatty acid selected from among omega-3fatty acids, omega-6 fatty acids and conjugated fatty acids.
 22. Thepre-emulsion composition of claim 21, wherein the non-polar activeingredient contains a polyunsaturated fatty acid selected from among adocosahexaenoic acid (DHA), an eicosapentaenoic acid (EPA), a fish oil,a flaxseed oil, a borage oil, an alpha-linolenic acid (ALA), agamma-linolenic acid (GLA), a conjugated linolenic acid (CLA), and a sawpalmetto extract.
 23. The method of claim 3, wherein the ingredientsinclude the non-polar solvent that dissolves the non-polar activeingredient and differs therefrom, wherein the amount of solvent issufficient to dissolve the non-polar active ingredient.
 24. The methodof claim 23, wherein the non-polar solvent comprises a Vitamin E oil, aflaxseed oil or a combination thereof.
 25. The method of claim 23,wherein the amount of the non-polar solvent is between 1% and 6% of thecomposition.
 26. The method of claim 3, wherein heating comprisesheating the ingredients to 40° C. to 60° C.
 27. The method of claim 3,wherein the homogenizing is performed with a reversible homogenizer. 28.The method of claim 3, wherein the ingredients include a co-surfactantin an amount sufficient to stabilize the composition.
 29. The method ofclaim 28, wherein the co-surfactant contains a phospholipid.
 30. Themethod of claim 29, wherein the phospholipid comprisesphosphatidylcholine.
 31. The method of claim 2, wherein the ingredientsinclude at least one preservative in an amount sufficient to preservethe composition.
 32. The method of claim 3, wherein the ingredientsinclude an emulsion stabilizer in an amount sufficient to stabilize thecomposition.
 33. The method of claim 4, wherein the non-polar activeingredients contain a polyunsaturated fatty acid selected from among adocosahexaenoic acid (DHA), an eicosapentaenoic acid (EPA), a fish oil,a flaxseed oil, a borage oil, an alpha-linolenic acid (ALA), agamma-linolenic acid (GLA), a conjugated linolenic acid (CLA), and a sawpalmetto extract.
 34. The method of claim 31, wherein the PEG-derivativeof Vitamin E is a tocopherol polyethylene glycol diester (TPGD).
 35. Themethod of claim 34, wherein the TPGD is selected from among tocopherolpolyethylene glycol succinate (TPGS), tocopherol sebacate polyethyleneglycol, tocopherol dodecanodioate polyethylene glycol, tocopherolsuberate polyethylene glycol, tocopherol azelaate polyethylene glycol,tocopherol citraconate polyethylene glycol, tocopherol methylcitraconatepolyethylene glycol, tocopherol itaconate polyethylene glycol,tocopherol maleate polyethylene glycol, tocopherol glutaratepolyethylene glycol, tocopherol glutaconate polyethylene glycol, andtocopherol phthalate polyethylene glycol, or a TPGS analog.
 36. Themethod of claim 35, wherein the TPGD is a TPGS-1000 or D-αTPGS.
 37. Themethod of claim 3, wherein the PEG-derivative of Vitamin E contains aPEG moiety selected from among any one or more of PEG-OH, PEG-NHS,PEG-aldehyde, PEG-SH, PEG-NH₂, PEG-CO₂H, methylated PEGs (m-PEGs) andbranched PEGs.
 38. The method of claim 3, wherein the PEG-derivative ofVitamin E contains a PEG moiety having a molecular weight of between 200Daltons or about 200 Daltons to 20,000 Daltons or about 20,000 Daltons,between 200 Daltons or about 200 Daltons and 6000 Daltons or about 6000Daltons, between 600 Daltons or about 600Daltons and 6000 Daltons orabout 6000 Daltons, between 200 Daltons or about 200 Daltons and 2000Daltons or about 2000 Daltons, between 600 Daltons or about 600 Daltonsand 1500 Daltons or about 1500 Daltons, or between 600 Daltons or about600 Daltons and 1000 or about 1000 Daltons.
 39. A method of providing anoil-based additive in a beverage, comprising: adding a pre-emulsioncomposition of claim 1, to a beverage, in an amount whereby: thebeverage contains an effective amount of the non-polar ingredient. 40.The method of claim 39, wherein the non-polar active ingredient isselected from among an omega-3 fatty acid, an omega-6 fatty acid, aconjugated fatty acid and a saw palmetto extract.
 41. The method ofclaim 39, wherein the non-polar active ingredient is selected from amongcoenzyme Q10, a docosahexaenoic acid (DHA), an eicosapentaenoic acid(EPA), a fish oil, a flaxseed oil, a borage oil, an alpha-linolenic acid(ALA), a gamma-linolenic acid (GLA), a conjugated linolenic acid (CLA)and a saw palmetto extract.
 42. The method of claim 39, furthercomprising heating the pre-emulsion composition, the beverage, or boththe pre-emulsion composition and the beverage, prior to addition of thepre-emulsion composition to the beverage.
 43. The method of claim 39,further comprising heating the mixture of the beverage and thepre-emulsion composition.
 44. The method of claim 42, wherein theheating comprises heating to at least 40° C. or at least about 40° C.;or at least 120° F. or about 120° F.
 45. The method of claim 39, furthercomprising cooling the beverage to at least 25° C. or about 25° C. 46.The method of claim 39, wherein the beverage is water, soda, milk, juiceor a sports nutrition beverage.
 47. The method of claim 39, wherein thebeverage containing the additive is about as clear as the beverage inthe absence of the additive.
 48. The pre-emulsion composition of claim1, wherein the PEG-derivative of Vitamin E contains a PEG moiety havinga molecular weight of between about 200 Daltons and about 6000 Daltons,between about 600 Daltons and about 6000Daltons, between about 200Daltons and about 2000 Daltons, between about 600 Daltons and about 1500Daltons, or between about 600 Daltons and about 1000 Daltons.
 49. Thepre-emulsion composition of claim 5, wherein the polyethylene glycol(PEG)-derivative of Vitamin E is a tocopherol polyethylene glycoldiester (TPGD).
 50. The pre-emulsion composition of claim 49, whereinthe TPGD is selected from among tocopherol polyethylene glycol succinate(TPGS), tocopherol sebacate polyethylene glycol, tocopheroldodecanodioate polyethylene glycol, tocopherol suberate polyethyleneglycol, tocopherol azelaate polyethylene glycol, tocopherol citraconatepolyethylene glycol, tocopherol methylcitraconate polyethylene glycol,tocopherol itaconate polyethylene glycol, tocopherol maleatepolyethylene glycol, tocopherol glutarate polyethylene glycol,tocopherol glutaconate polyethylene glycol, and tocopherol phthalatepolyethylene glycol, or a TPGS analog.
 51. The pre-emulsion compositionof claim 50, wherein the TPGD is TPGS.
 52. The pre-emulsion compositionof claim 51, wherein the TPGS is TPGS-1000 or D-α TPGS.
 53. Thepre-emulsion composition of claim 5, wherein the non-polar ingredient isa coenzyme Q10 compound.
 54. The pre-emulsion composition of claim 1,wherein the amount of the non-polar ingredient is between 10% and 30%,by weight of the composition.
 55. The pre-emulsion composition of claim6, wherein the PEG-derivative of vitamin E is a tocopherol polyethyleneglycol succinate (TPGS).
 56. The pre-emulsion composition of claim 7,wherein the PEG-derivative of vitamin E is a tocopherol polyethyleneglycol succinate (TPGS).
 57. The pre-emulsion composition of claim 55,wherein the TPGS is TPGS-1000.
 58. The pre-emulsion composition of claim56, wherein the TPGS is TPGS-1000.
 59. The pre-emulsion composition ofclaim 9, wherein the TPGS is TPGS-1000.
 60. The method of claim 2,wherein the PEG-derivative of vitamin E is a tocopherol polyethyleneglycol succinate (TPGS).
 61. The method of claim 60, wherein the TPGS isTPGS-1000.
 62. The method of claim 4, wherein the PEG-derivative ofvitamin E is a tocopherol polyethylene glycol succinate (TPGS).
 63. Themethod of claim 62, wherein the TPGS is TPGS-1000.